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US20020198207A1 - Novel Hexanoic acid derivatives - Google Patents

Novel Hexanoic acid derivatives Download PDF

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US20020198207A1
US20020198207A1 US10/154,145 US15414502A US2002198207A1 US 20020198207 A1 US20020198207 A1 US 20020198207A1 US 15414502 A US15414502 A US 15414502A US 2002198207 A1 US2002198207 A1 US 2002198207A1
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alkyl
hydroxy
amide
carboxylic acid
benzyl
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US10/154,145
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John Kath
Matthew Brown
Christopher Poss
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Priority claimed from US09/380,269 external-priority patent/US6403587B1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/28—Cinnolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel hexanoic acid derivatives, methods of use and pharmaceutical compositions containing them.
  • the compounds of the invention are potent and selective inhibitors of MIP-1 ⁇ binding to its receptor CCR1 found on inflammatory and immunomodulatory cells (preferably leukocytes and lymphocytes).
  • CCR1 found on inflammatory and immunomodulatory cells (preferably leukocytes and lymphocytes).
  • the CCR1 receptor is also sometimes referred to as the CC-CKR1 receptor.
  • MIP-1 ⁇ and the related chemokine shown to interact with CCR1 (e.g., RANTES and MCP-3)) induced chemotaxis of THP-1 cells and human leukocytes and are potentially useful for the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult Respiratory Distress Syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), transplantation tissue rejection (chronic and acute), organ rejection (chronic and acute), atherosclerosis,
  • MIP-1 and RANTES are soluble chemotactic peptides (chemokines) which are produced by inflammatory cells, in particular CD8+ lymphocytes, polymorphonuclear leukocytes (PMNs) and macrophages, J.Biol. Chem., 270 (30) 29671-29675 (1995). These chemokines act by inducing the migration and activation of key inflammatory and immunomodulatory cells. Elevated levels of chemokines have been found in the synovial fluid of rheumatoid arthritis patients, chronic and rejecting tissue transplant patients and in the nasal secretions of allergic rhinitis patients following allergen exposure (Teran , et al., J.
  • PCT publication WO 93/025057 published Feb. 4, 1993, refers to dipeptide analogs which are claimed to inhibit retroviral proteases.
  • PCT publication WO 92/17490 published Oct. 15, 1992, refers to peptides containing at least one O-phosphate monoester or diester. The compounds are claimed to possess activity for inhibiting retroviruses.
  • the present invention relates to compounds of the formula
  • R 1 is (C 2 -C 9 )heteroaryl optionally substituted with one or more substituents (preferably one to three substituents) independently selected from the group consisting of hydrogen, halo, CN, (C 1 -C 6 )alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, HO—(C ⁇ O)—, (C 1 -C 6 )alkyl-O—(C ⁇ O)—, HO—(C ⁇ O)—(C 1 -C 6 )alkyl, (C 1 -C 8 )alkyl-O—(C ⁇ O)——
  • R 2 is phenyl-(CH 2 ) m —, naphthyl-(CH 2 ) m —, (C 3 -C 10 )cycloalkyl-(CH 2 ) m —, (C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl-(CH 2 ) m —, wherein m is an interger from zero to four, wherein each of said phenyl, naphthyl, (C 3 -C 10 )cycloalkyl or (C 2 -C 9 )heteroaryl moieties of said phenyl-(CH 2 ) m —, naphthyl-(CH 2 ) m —, (C 3 -C 10 )cycloalkyl-(CH 2 ) m — or (C 2 -C 9 )heteroaryl-(CH 2 ) m — groups may optionally be substituted with one or more
  • R 3 is hydrogen, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl-(CH 2 ) n —, (C 2 -C 9 )heterocycloalkyl-(CH 2 ) n —, (C 2 -C 9 )heteroaryl-(CH 2 ) n — or aryl-(CH 2 ) n —; wherein n is an interger from zero to six;
  • R 3 (C 1 -C 10 )alkyl group may optionally be substituted with one or more substituents, (preferably from one to three substituents) independently selected from hydrogen, halo, CN, (C 1 -C 6 )alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, HO—(C ⁇ O)—, (C 1 -C 6 )alkyl-O—(C ⁇ O)—, HO—(C ⁇ O)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(C ⁇ O)—(C ⁇ O)—(C
  • the (C 3 -C 10 )cycloalkyl moiety of said R 3 (C 3 -C 10 )cycloalkyl-(CH 2 ) n — group may optionally be substituted by one to three substitutents independently selected from the group consisting of hydrogen, halo, CN, (C 1 -C 6 )alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, HO—(C ⁇ O)—, (C 1 -C 6 )alkyl-O—(C ⁇ O)—, HO—(C ⁇ O)—(C 1 -C 6 )alkyl
  • the (C 2 -C 9 )heterocycloalkyl moiety of said R 3 (C 2 -C 9 )heterocycloalkyl-(CH 2 ) n — group may contain from one to three heteroatoms independently selected from nitrogen, sulfur, oxygen, >S( ⁇ O), >SO 2 or >NR 6 , wherein said (C 2 -C 9 )heterocycloalkyl moiety of said (C 2 -C 9 )heterocycloalkyl-(CH 2 ) n — group may optionally be substituted on any of the ring carbon atoms capable of forming an additional bond (preferably one to three substitutents per ring) with a substituent independently selected from the group consisting of hydrogen, halo, CN, (C 1 -C 6 )alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C 1 -C 6 )al
  • the (C 2 -C 9 )heteroaryl moiety of said R 3 (C 2 -C 9 )heteroaryl-(CH 2 ) n — group may contain from one to three heteroatoms independently selected from nitrogen, sulfur or oxygen, wherein said (C 2 -C 9 )heteroaryl moiety of said (C 2 -C 9 )heteroaryl-(CH 2 ) r — group may optionally be substituted on any of the ring carbon atoms capable of forming an additional bond (preferably one to three substitutents per ring) with a substituent selected from the group consisting of hydrogen, halo, CN, (C 1 -C 6 )alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy optionally substituted with one or more fluorine atom
  • said aryl moiety of said R 3 aryl-(CH 2 ) n — group is optionally substituted phenyl or naphthyl, wherein said phenyl and naphthyl may optionally be substituted with from one to three substituents independently selected from the group consisting of hydrogen, halo, CN, (C 1 -C 6 )alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, HO—(C ⁇ O)—, (C 1 -C 6 )alkyl-O—(C ⁇ O)—, HO—(C ⁇ O)—(C 1 -C 6 )
  • R 3 and the carbon to which it is attached form a five to seven membered carbocyclic ring, wherein any of the carbon atoms of said five membered carbocyclic ring may optionally be substituted with a substituent selected from the group consisting of hydrogen, halo, CN, (C 1 -C 6 )alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, HO—(C ⁇ O)—, (C 1 -C 6 )alkyl-O—(C ⁇ O)—, HO—(C ⁇ O)—(C 1 -C 6 )alkyl, (C
  • R 4 is hydrogen, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C ⁇ O)—, (C 3 -C 10 )cycloalkyl-(CH 2 ) p —, (C 2 -C 9 )heterocycloalkyl-(CH 2 ) p —, (C 2 -C 9 )heteroaryl-(CH 2 ) p —, phenyl-(CH 2 ) p —, or naphthyl-(CH 2 ) p —, wherein p is an integer from zero to four; wherein said (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl, phenyl and naphthyl groups of said (C 2 -C 9 )hetero
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a (C 2 -C 9 )heterocycloalkyl group wherein any of the ring atoms of said (C 2 -C 9 )heterocycloalkyl group may optionally be substituted, preferably from zero to two substituents, with a substituent selected from the group consisting of hydrogen, halo, CN, (C 1 -C 6 )alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, HO—(C ⁇ O)—, (C 1 -C 6 )alkyl-O—
  • R 5 is hydrogen, (C 1 -C 6 )alkyl or amino
  • R 6 is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(CH 2 ) g —, (C 1 -C 6 )alkoxy(C ⁇ O)—(CH 2 ) g —, (C 1 -C 6 )alkyl-(SO 2 )—(CH 2 ) 9 —, (C 6 -C 10 )aryloxy-(CH 2 ) 9 —, (C 6 -C 10 )aryloxy(C ⁇ O)—(CH 2 ) 9 —, or (C 1 -C 10 )aryl-(SO 2 )—(CH 2 ) 9 —, wherein g is an integer from zero to four;
  • R 4 or R 5 when one of R 4 or R 5 is hydrogen, and the other of R 4 or R 5 is (C 1 -C 6 )alkyl;
  • R 2 is (C 3 -C 10 )cycloalkyl or isopropyl and
  • R 3 is (C 3 -C 5 )alkyl, phenyl, methylvinyl, dimethylvinyl, halovinyl, hydroxy(C 1 -C 3 )alkyl or amino(C 1 -C 4 )alkyl then R 1 must be other than indol-5-yl, 6-azaindol-2-yl, 2,3-dichloro-pyrrol-5-yl, 4-hydroxyquinolin-3-yl, 2-hydroxyquinoxalin-3-yl, 6-azaindolin-3-yl, or optionally substituted indol-2 or 3-yl;
  • the present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I.
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
  • the invention also relates to base addition salts of formula I.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • the compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof.
  • alkyl and alkenyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic moieties.
  • halogen includes fluorine, chlorine, bromine, and iodine.
  • (C 3 -C 10 )Cycloalkyl when used herein refers to cycloalkyl groups containing zero to two levels of unsaturation such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1 ]octane, norbornanyl etc.
  • (C 2 -C 9 )Heterocycloalkyl when used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,
  • (C 2 -C 9 )Heteroaryl when used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7
  • Aryl when used herein refers to phenyl or naphthyl.
  • the compounds of this invention include all conformational isomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e.g., enantiomers and diastereomers), as well as racemic, diastereomeric and other mixtures of such isomers.
  • Preferred compounds of the of formula I include those with the stereochemistry depicted in formula
  • Preferred compounds of the formula I include those wherein R 1 is optionally substituted pyrazolo[3,4-b]pyridinyl, cinnolinyl, pyridinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzothiazolyl, indolyl, pyrazinyl, benzoimidazolyl, benzofuranyl, benzo[b]thiophenyl, naphthalenyl, quinoxalinyl, isoquinolinyl, 5,6,7,8-tetrahydro-quinolin-3-yl or quinolinyl, more preferably pyrazolo[3,4-b]pyridin-5-yl, cinnolin-4-yl, pyridin-2-yl, 6,7-dihydro-5H-[1]pyrindin-3-yl, benzothiazol-2-yl, indol-2-yl, pyrazin-2-y
  • R 2 is optionally substituted phenyl, benzyl, naphthyl, cyclohexyl, thienyl, thiazolyl, pyridyl, oxazolyl, furanyl, or thiophenyl; wherein said substituents are independently selected from hydrogen, halo, (C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, —C( ⁇ O)—OH, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C ⁇ O)—, NO 2 , amino, (C 1 -C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 amino, (C 1 -C 6 )alkyl-O—(C ⁇ O)—, HO—(C ⁇ O)—(C 1 -C 6 )alkyl, (C 1
  • R 3 is optionally substituted (C 1 -C 10 )alkyl, benzyl, pyranyl or (C 3 -C 10 )cycloalkyl-(CH 2 ) n —, wherein any of the carbon-carbon single bonds of said (C 1 -C 10 )alkyl may be optionally replaced by a carbon-carbon double bond; more preferably optionally substituted n-butyl, isobutyl, n-pentyl, 3-methyl-butyl, 2-methyl-pentyl, allyl, cyclopentyl, cyclohexyl or cycloheptyl, more preferably wherein the substituent is fluoro, (C 1 -C 6 )alkyl or hydroxy.
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-7-fluoro-1(S)-(3-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(2-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-4-(2,6-dimethyl-tetrahydro-pyran-4-yl)-2(S)-hydroxy-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-cyclohexylmethyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-(4,4-difluoro-1-hydroxy-cyclohexyl)-2(S)-(hydroxy-4-hydroxycarbamoyl-butyl )]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-4(S)-(4,4-difluoro-cyclohexyl)-2(S)-hydroxy-butyl]-amide;
  • quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiophen-2-ylmethyl-octyl)-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-7-chloro-2(S)-hydroxy-oct-6-enyl)]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-phenyl-pentyl)]-amide;
  • quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiazol-4-ylmethyl-octyl)-amide;
  • quinoxaline-2-carboxylic acid (4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-1-thiazol-4-ylmethyl-octyl)-amide
  • quinoxaline-2-carboxylic acid (7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-thiazol-4-ylmethyl-octyl)-amide
  • quinoxaline-2-carboxylic acid [4-carbamoyl-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-1-thiazol-4-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-thiazol-4-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-thiazol-4-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-1-thiazol-4-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-1-(3,5-difluoro-benzyl)-7-fluoro-2-hydroxy-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1-(3,5-difluoro-benzyl)-7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-1-(3,5-difluoro-benzyl)-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1-(3,5-difluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-1-(3,5-difluoro-benzyl)-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1-(3,5-difluoro-benzyl)-4-(4,4-difluoro-cyclohexyl )-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid (4-carbamoyl-2-hydroxy-7-methyl-1-pyridin-2-ylmethyl-octyl)-amide
  • quinoxaline-2-carboxylic acid (7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-pyridin-2-ylmethyl-octyl)-amide
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(2,6-dimethyl-tetrahydro-pyran-4-yl)-2-hydroxy-1-pyridin-2-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-pyridin-2-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid (4-carbamoyl-4-cyclohexyl-2-hydroxy-1-pyridin-2-ylmethyl-butyl)-amide
  • quinoxaline-2-carboxylic acid [4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-1-pyridin-2-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid (4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-1-pyridin-3-ylmethyl-octyl)-amide
  • quinoxaline-2-carboxylic acid (2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-pyridin-3-ylmethyl-octyl)-amide
  • quinoxaline-2-carboxylic acid [4-carbamoyl-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-1-pyridin-3-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-(2,6-dimethyl-tetrahydro-pyran-4-yl)-2-hydroxy-4-hydroxycarbamoyl-1-pyridin-3-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-pyridin-3-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid (4-cyclohexyl-2-hydroxy-4-hydroxycarbamoyl-1-pyridin-3-ylmethyl-butyl)-amide
  • quinoxaline-2-carboxylic acid [4-carbamoyl-7-fluoro-1-(4-fluoro-benzyl)-2-hydroxy-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [7-fluoro-1-(4-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-1-(4-fluoro-benzyl)-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1-(4-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-1-(4-fluoro-benzyl)-2-hydroxy-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-(4,4-difluoro-cyclohexyl)-1-(4-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-1-(3-fluoro-benzyl)-2-hydroxy-4-(1-hydroxy-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [7-fluoro-1-(3-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(2,6-dimethyl-tetrahydro-pyran-4-yl)-1-(3-fluoro-benzyl)-2-hydroxy-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1-(3-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-1-(3-fluoro-benzyl)-2-hydroxy-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-cyclohexyl-1-(3-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-1-(2-fluoro-benzyl)-2-hydroxy-4-(1-hydroxy-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [7-fluoro-1-(2-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(2,6-dimethyl-tetrahydro-pyran-4-yl)-1-(2-fluoro-benzyl)-2-hydroxy-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1-(2-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-1-(2-fluoro-benzyl)-2-hydroxy-butyl]-amide;
  • quinoxaline-2-carboxylic acid (4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-1-thiophen-2-ylmethyl-octyl)-amide
  • quinoxaline-2-carboxylic acid (7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-thiophen-2-ylmethyl-octyl)-amide
  • quinoxaline-2-carboxylic acid [4-carbamoyl-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-1-thiophen-2-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-thiophen-2-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-thiophen-2-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-1-thiophen-2-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-2-hydroxy-7-methyl-1-(3-trifluoromethyl-benzyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-(3-trifluoromethyl-benzyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-carbamoyl-4-(4-hydroxy-2,6-dimethyl-tetrahydro-pyran-4-yl)-1-(3-trifluoromethyl-benzyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-(3-trifluoromethyl-benzyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid ⁇ 4-hydroxycarbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-(3-trifluoromethyl-benzyl)-butyl ⁇ -amide;
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-carbamoyl-7-methyl-1-(3-trifluoromethoxy-benzyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [4-hydroxycarbamoyl-2-hydroxy-7-methyl-1-(3-trifluoromethoxy-benzyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-carbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-(3-trifluoromethoxy-benzyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(4-hydroxy-2,6-dimethyl-tetrahydro-pyran-4-yl)-1-(3-trifluoromethoxy-benzyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid ⁇ 4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-(3-trifluoromethoxy-benzyl)-butyl ⁇ -amide;
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-carbamoyl-7-methyl-1-(4-trifluoromethoxy-benzyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-(4-trifluoromethoxy-benzyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-carbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-(4-trifluoromethoxy-benzyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-(4-trifluoromethoxy-benzyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid ⁇ 4-hydroxycarbamoyl-4-(4,4-difluoro-cyclohexyl )-2-hydroxy-1-(4-trifluoromethoxy-benzyl)-butyl ⁇ -amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-2-hydroxy-7-methyl-1-(2-trifluoromethyl-benzyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-(2-trifluoromethoxy-benzyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-carbamoyl-4-(4-hydroxy-2,6-dimethyl-tetrahydro-pyran-4-yl)-1-(2-trifluoromethoxy-benzyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-(2-trifluoromethoxy-benzyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid ⁇ 4-hydroxycarbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-(2-trifluoromethoxy-benzyl)-butyl ⁇ -amide;
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-carbamoyl-7-methyl-1-[3-(1-hydroxy-1-methyl-ethyl)-benzyl]-octyl]-amide;
  • quinoxaline-2-carboxylic acid [4-hydroxycarbamoyl-2-hydroxy-7-methyl -1-[3-(1-hydroxy-1-methyl-ethyl)-benzyl]-octyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-carbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-[3-(1-hydroxy-1-methyl-ethyl)-benzyl]-butyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(4-hydroxy-2,6-dimethyl-tetrahyd ro-pyran-4-yl)-1-3-(1-hydroxy-1-methyl-ethyl)-benzyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid ⁇ 4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-[3-(1-hydroxy-1-methyl-ethyl)-benzyl]-butyl ⁇ -amide;
  • quinoxaline-2-carboxylic acid ⁇ 4-hydroxycarbamoyl-4-(cyclohexyl)-2-hydroxy-1-[3-(1-hydroxy-1-methyl-ethyl)-benzyl]-butyl ⁇ -amide;
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-carbamoyl-7-methyl-1-thiophen-3-ylmethyl-butyl]-amide
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-thiophen-3-ylmethyl-butyl]-amide
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-carbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-thiophen-3-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-thiophen-3-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-thiophen-3-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4-hydroxycarbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-thiophen-3-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide;
  • quinoxaline-2-carboxylic acid (6-chloro-1(S)-cyclohexyl methyl-2(S)-hydroxy-4(S)-methylcarbamoyl-hept-6-enyl)-amide;
  • quinoxaline-2-carboxylic acid 1(S)-sec-butyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide;
  • quinoxaline-2-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-hept-6-enyl)-amide;
  • quinoxaline-2-carboxylic acid 1(S)-cyclohexylmethyl-4(R)-dimethylcarbamoyl-2(S)-hydroxy-6-methyl-hept-6-enyl)-amide;
  • quinoxaline-2-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-4(R)-methylcarbamoyl-5-phenyl-pentyl)-amide;
  • quinoxaline-2-carboxylic acid [1-(4-benzyloxy-benzyl)-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(S)-methylcarbamoyl-heptyl)-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide;
  • quinoxaline-2-carboxylic acid [2(S)-hydroxy-1(S)-(4-methoxy-benzyl)-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide;
  • quinoxaline-2-carboxylic acid [2(S)-hydroxy-1(S)-(4-hydroxy-benzyl)-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide;
  • quinoxaline-2-carboxylic acid (5-cyclohexyl-1(S)-cyclohexylmethyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide;
  • quinoxaline-2-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;
  • quinoxaline-2-carboxylic acid [1(S)-(4-fluoro-benzyl)-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-butylcarbamoyl-2(S)-hydroxy-7-methyl-octyl)-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-5-cyclopentyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-5-cyclopentyl-2(S)-hydroxy-pentyl)-amide;
  • quinoxaline-2-carboxylic acid [1(S)-(4,4-difluoro-cyclohexylmethyl)-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-(4,4-difluoro-cyclohexylmethyl)-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-propylcarbamoyl-octyl)-amide;
  • quinoxaline-2-carboxylic acid [1(S)-(4-difluoromethoxy-benzyl)-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-butylcarbamoyl-5-cyclopentyl-2(S)-hydroxy-pentyl)-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-8-methyl-4(R)-methylcarbamoyl-nonyl)-amide;
  • quinoxaline-2-carboxylic acid (2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-1(S)-naphthalen-2-ylmethyl-heptyl)-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-5-(4,4-difluoro-cyclohexyl)-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-5-(4,4-difluoro-cyclohexyl)-2(S)-hydroxy-pentyl]-amide;
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-oct-6-enyl)-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-nonyl)-amide;
  • quinoxaline-2-carboxylic acid [7-fluoro-1(S)-(4-fluoro-benzyl)-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3,4-dichloro-benzyl)-7-fluoro-2(S)-hydroxy-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-phenethyl-octyl)-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(4-methyl-piperazine-1-carbonyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(morpholine-4(R)-carbonyl )-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(3-morpholin-4-yl-propionyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-3-(2-carbamoyl-indan-2-yl)-2(S)-hydroxy-propyl]-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-4(R)-methylcarbamoyl-7-phenyl-hept-6-enyl)-amide;
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1-(2(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-I (S)-(2(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-4(S)-(4-isopropyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiophen-2-ylmethyl-octyl)-amide;
  • quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiazol-4(R)-ylmethyl-octyl)-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4(S)-(3,3,5,5-tetramethyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-6-chloro-2(S)-hydroxy-4(S)-methylcarbamoyl-hept-6-enyl)-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-6-cyclopropyl-2(S)-hydroxy-hexyl)-amide;
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-6-cyclopropyl-2(S)-hydroxy-4(R)-methylcarbamoyl-hexyl)-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-4(S)-(4-methyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-(4-trifluoromethoxy-phenyl)-pentyl]-amide;
  • quinoxaline-2-carboxylic acid [1-benzyl-4(R)-carbamoyl-5-(4-fluoro-phenyl)-2(S)-hydroxy-pentyl]-amide;
  • quinoxaline-2-carboxylic acid [2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-1(S)-(4-methylcarbamoyl-benzyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4(S)-(tetrahydro-pyran-4-yl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(2(R)-pyridin-2-yl-ethylcarbamoyl )-octyl]-amide; quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-(3,4-dimethoxy-benzylcarbamoyl)-7-fluoro-2(S)-hydroxy-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-4(S)-(3,5-dimethyl-cyclohexyl)-2(S)-hydroxy-butyl]-amide; quinoxaline-2-carboxylic acid ⁇ 1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-[(pyridin-2-ylmethyl)-carbamoyl]-octyl ⁇ -amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4-(2-ethylsulfanyl-ethylcarbamoyl)-7-fluoro-2(S)-hydroxy-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-(2-methoxy-ethylcarbamoyl)-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(2-pyridin-3-yl-ethylcarbamoyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(2-pyridin-4(R)-yl-ethylcarbamoyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-4-(1,1-dioxo-hexahydro-thiopyran-4-yl)-2(S)-hydroxy-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-(2-methoxy-benzylcarbamoyl)-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-(3-methoxy-benzylcarbamoyl)-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(2-thiophen-2-yl-ethylcarbamoyl)-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-(4-methoxy-benzylcarbamoyl)-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-(2(S)-hydroxymethyl-pyrrolidine-1-carbonyl)-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4-carbamoyl-4(S)-(4,4-difluoro-cyclohexyl)-2(S)-hydroxy-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-(2,3-dimethoxy-benzylcarbamoyl)-7-fluoro-2(S)-hydroxy-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-4-(2,6-dimethyl-tetrahydro-pyran-4-yl)-2(S)-hydroxy-butyl]-amide;
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-7-fluoro-1(S)-(3-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-1-(4-iodo-benzyl)-7-methyl-octyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid (4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-1-phenyl-octyl)-amide
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-cyclohexyl)-1(S)-thiophen-2-ylmethyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(4-hydroxy-tetrahydro-thiopyran-4-yl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl)-amide
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-5-(2-chloro-phenyl)-2(S)-hydroxy-pentyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-cyclopentyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-5-(3,4-dichloro-phenyl)-2(S)-hydroxy-pentyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-cyclopentyl)-butyi]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-3-methyl-cyclopentyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-3,5-dimethyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-3,5-dimethyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-cycloheptyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-cycloheptyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-5-(3-fluoro-phenyl)-2(S)-hydroxy-pentyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(2-hydroxy-adamantan-2-yl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(9-hydroxy-bicyclo[3.3.1 ]non-9-yl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-(2-hydroxy-adamantan-2-yl)-4-hydroxycarbamoyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-(9-hydroxy-bicyclo[3.3.1 ]non-9-yl)-4-hydroxycarbamoyl-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-(3-methoxy-phenyl)-pentyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-4-propyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-4-propyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-(4-methoxy-phenyl)-pentyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-4(S)-(4-ethyl-1-hydroxy-cyclohexyl)-2-hydroxy-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-4,4-dimethyl-cyclohexyl)-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-4,4-dimethyl-cyclohexyl )-but yl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-butyl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-(4,4-difluoro-1-hydroxy-cyclohexyl)-2(S)-hydroxy-4-hydroxycarbamoyl-but yl]-amide;
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-4-trifluoromethyl-cyclohexyl)-butyl]-amide.
  • the present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis).
  • autoimmune diseases such as rheumatoi
  • the present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by inhibiting MIP-1 ⁇ binding to the receptor CCR1 in a mammal, preferably a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by inhibiting MIP-1 ⁇ binding to the receptor CCR1 in a mammal, preferably a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier.
  • disorders and conditions are those enumerated in the preceding paragraph.
  • the present invention also relates to a method for treating or preventing a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis) in a mammal, preferably a human
  • the present invention also relates to a method for treating or preventing a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal, preferably a human, comprising administering to a mammal in need of such treatment or prevention an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder or condition.
  • the present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis) in a mammal, preferably a autoimmune diseases
  • the present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal, preferably a human, comprising a CCR1 receptor antagonizing effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also relates to a method for treating or preventing a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis) in a mammal, preferably a human
  • This invention also encompasses pharmaceutical compositions containing and methods of treating or preventing comprising administering prodrugs of compounds of the formula I.
  • Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula I.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain.
  • Prodrugs also include compounds of formula I in which the secondary amide and its ⁇ -hydroxy when taken together form a group of the formula
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined in formula I and U and V are independently carbonyl, methylene, SO 2 or SO 3 , and b is an integer from one to three wherein each methylene group is optionally substituted with hydroxy.
  • Scheme 1 refers to the preparation of compounds of the formula I having the exact stereochemistry
  • compounds of the formula I wherein either or both R 4 or R 5 are other than hydrogen, are prepared from compounds of the formula II (i.e. IIa and IIb) by reaction with a compound of the formula R 4 R 5 NH in a polar solvent at a temperature from about 0° C. to about 100° C., preferably the boiling point of the solvent used, i.e. 65° C. when methanol is the solvent.
  • Suitable solvents include, alcohols, such as methanol, ethanol, or butanols or ethers such as glyme or dioxane (an acid catalyst is preferably used with an ether solvent).
  • the solvent is dioxane.
  • compounds of formula I wherein either or both R 4 and R 5 are hydrogen, can be prepared from compounds of formula II, (i.e. IIa and IIb) by reaction with ammonia or another volatile amine in a polar solvent at a temperature from about ⁇ 10° C. to about 35° C., preferably at about 30° C.
  • Suitable solvents include, alcohols, such as methanol, ethanol, or butanols; or ethers such as glyme or dioxane (an acid catalyst may be used with an ether solvent).
  • the solvent is methanol.
  • Compounds of formula II are prepared by coupling a compound of formula III (i.e. IIIa and IIIb) with an acid of the formula R 1 CO 2 H. Such a coupling reaction is generally conducted at a temperature of about ⁇ 30° C. to about 80° C., preferably about 0° C. to about 25° C.
  • Suitable coupling reagents which activate the carboxylic acid functionality are dicyclohexylcarbodiimide/hydroxybenzotriazole (DCC/HBT), N-3-dimethylaminopropyl-N′-ethylcarbodiimide (EDC)/HBT, 2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyl diimidazole (CDI)/dimethylaminopyridine (DMAP), and diethylphosphorylcyamide.
  • the coupling is conducted in an inert solvent, preferably an aprotic solvent, such as acetonitirile, dichloromethane, chloroform, and dimethylformamide.
  • the preferred solvent is dichloromethane.
  • the protecting group, P, of the compound of the formula IV is carbobenzyloxy
  • the latter may be removed by hydrogenation with a nobel metal catalyst such as palladium or palladium hydroxide on carbon in the presence of hydrogen.
  • the hydrogenation is generally conducted at a temperature of about 0° C. to about 100° C., preferably about 20° C. to 50° C.
  • the protecting group, P is t-butoxycarbonyl group
  • acidolysis may be conducted with HCl in dioxane or with trifluoracetic acid in methylene chloride at a temperature of about ⁇ 30° C. to about ⁇ 70° C., preferably about ⁇ 5° C. to about 35° C.
  • the protecting group, P is 9-fluorenylmethylenoxycarbonyl
  • such group may be removed by treatment with an amine base, preferably piperidine. This reaction may be run in piperidine as solvent at 10° C. to about 100° C., preferably at 25° C.
  • Compounds of the formula III, wherein R 3 is substituted (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl-(CH 2 ) n — or (C 2 -C 9 )heterocycloalkyl-(CH 2 ) n — may be prepared from compounds of the formula IV, wherein R 3 is (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl-(CH 2 ) n — or (C 2 -C 9 )heterocycloalkyl-(CH 2 ) n —, wherein one of the carbon-carbon single bonds is replaced by a carbon-carbon double bond, by methods well known to those of ordinary skill in the art.
  • a compound of formula III, wherein R 3 is (C 1 -C 10 )alkyl substituted by one to three fluoro groups can be prepared from compounds of the formula IV, wherein R 3 is (C 1 -C 10 )alkyl, wherein one of the carbon-carbon single bonds of said (C 1 -C 10 )alkyl has been replaced by a carbon-carbon double bond, by reaction with hydrogen fluoride in pyridine (i.e. pyridinium poly(hydrogen fluoride), in a reaction inert solvent.
  • Suitable solvents include cyclohexane, toluene or benzene, preferably benzene.
  • the aforesaid reaction is run at a temperature from about ⁇ 78° C. to about 35° C.
  • this reaction is carried out in benzene at about 25° C.
  • Suitable leaving groups include chloro, fluoro, bromo, iodo, mesylate, triflate or tosylate.
  • the leaving group is a triflate, iodide or bromide.
  • Triflates may be easily prepared according to the method of Beard, et al., J Org Chem., 38, 3673 (1973).
  • Suitable bases include lithium dialkyl amides such as lithium N-isopropyl-N-cyclohexylamide or potassium hydride.
  • Suitable solvents include ethers (such as THF, glyme or dioxane) benzene or toluene, preferably THF. The aforesaid reaction is conducted at about ⁇ 78° C. to about 0° C., preferably at about ⁇ 78° C.
  • compounds of the formula IV wherein R 3 is (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl-(CH 2 ) n — or (C 2 -C 9 )heterocycloalkyl-(CH 2 ) n — can be prepared by reaction of a compound of formula V with an aldehyde or ketone precursor of R 3 in an aldol condensation.
  • a compound of the formula V can be reacted with a compound of the formula R 3 ( ⁇ O) in the presence of a base, to form an aldol intermediate of the formula
  • the compound of formula VI may be converted into the compound of formula IV by the elimination of water using techniques which are familiar to those skilled in the art, for example, by heating to the reflux temperature a solution of the compound of formula VI in a solvent such as benzene, toluene or xylene, in the presence of a catalytic amount of phosphorous pentoxide, benzene- or p-toluene-sulfonic acid with provision for the removal of the water generated, preferably (methoxycarbonylsulfamoyl)-triethylammonium hydroxide (Burgess reagent).
  • a solvent such as benzene, toluene or xylene
  • a catalytic amount of phosphorous pentoxide, benzene- or p-toluene-sulfonic acid with provision for the removal of the water generated, preferably (methoxycarbonylsulfamoyl)-triethylammonium hydro
  • the aldol reaction is typically carried out in a polar solvent such as DMSO, DMF, tetrahydrofuran (THF), methanol or ethanol, at a temperature from about ⁇ 78° C. to about 80° C.
  • a polar solvent such as DMSO, DMF, tetrahydrofuran (THF), methanol or ethanol
  • THF tetrahydrofuran
  • methanol methanol
  • ethanol ethanol
  • Suitable bases for use in the aldol formation step include potassium carbonate (K 2 CO 3 ), sodium carbonate (Na 2 CO 3 ), sodium hydride (NaH), sodium methoxide, potassium-tert.-butoxide, lithium diisopropylamide, pyrrolidine and piperidine. Lithium diisopropylamide is preferred.
  • Compounds of the formula IV wherein R 3 is unsaturated can be converted to saturated analogues by hydrogenating the compounds containing a carbon-carbon double bond, using standard techniques that are well known to those skilled in the art. For example, reduction of the double bond may be effected with hydrogen gas (H 2 ), using catalysts such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO 4 ), platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), in an appropriate solvent such as methanol, ethanol, THF, dioxane or ethyl acetate, at a pressure from about 1 to about 5 atmospheres and a temperature from about 10° C.
  • H 2 hydrogen gas
  • catalysts such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO 4 ), platinum on carbon (Pt/C
  • An alternative procedure employing the use of reagents such as ammonium formate and Pd/C in methanol at the reflux temperature under an inert atmosphere (e.g., nitrogen or argon gas) is also effective in reducing the carbon-carbon double bond of compounds of the formula I.
  • Another alternative method involves selective reduction of the carbon-carbon bond. This can be accomplished using samarium and iodine or samarium iodide (Sml 2 ) in methanol or ethanol at about room temperature, as described by R. Yanada et. al., Synlett., 443-4 (1995).
  • Compounds of the formula V can be prepared by methods well known to those of ordinary skill in the art or are commercially available. Specifically, compounds of the formula Va and Vb (shown below) can be prepared by the method of Fray et al., ( J. Org. Chem., 51, 4828-4833 (1986)) using an (S)-aldehyde of the formula
  • Compounds of the formula VII are prepared by reducing amino acids or amino esters to alcohols (Stanfield et al., J. Org. Chem. 46, 4799-4800 (1981), Soai et al., Bull. Chem. Soc. Jpn., 57, 2327 (1984)) followed by oxidation of the alcohols to aldehydes of the formula VII (Luly et al., J.Orq. Chem., 53 (26), 6109-6112 (1988) and Denis et al., J Orq. Chem., 56 (24), 6939-6942 (1991).).
  • Un-natural amino acids can be prepared according to the method of Myers et al., Tet. Lett. 36, (1995) and Myers et al. J. Am. Chem. Soc., 117, 8488-8489 (1995).
  • Aldehyde or ketone precursors of the group R 3 are commercially available (e.g., -cyclohexanone) or can be made by methods well known to those of ordinary skill in the art, such as described in J. Am. Chem. Soc., 90, 7001 (1968) and J. Ore. Chem., 40, 574 (1975).
  • the pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere).
  • the compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
  • non-toxic acid addition salts i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphat
  • Those compounds of the formula I which are also acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations.
  • Such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I. These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc.
  • salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields.
  • the active compounds are potent antagonists of the CCR1 receptors.
  • the active compounds are useful in the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous
  • autoimmune diseases such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel
  • the activity of the compounds of the invention can be assessed according to procedures know to those of ordinary skill in the art. Examples of recognized methods for determining CCR1 induced migration can be found in Coligan, J. E., Kruisbeek, A. M., Margulies, D. H., Shevach, E. M., Strober, W. editors: Current Protocols In Immunology, 6.12.1-6.12.3. (John Wiley and Sons, NY, 1991). One specific example of how to determine the activity of a compound for inhibiting migration is described in detail below.
  • THP-1 cells ATCC TIB-202
  • primary human monocytes or primary lymphocytes
  • Compound dilutions can be prepared using standard serological techniques and are mixed with cells prior to adding to the chamber.
  • the chamber is removed, the cells in the upper chamber aspirated, the upper part of the filter wiped and the number of cells migrating can be determined according to the following method.
  • the chamber (a 96 well variety manufactured by Neuroprobe) can be centrifuged to push cells off the lower chamber and the number of cells can be quantitated against a standard curve by a color change of the dye fluorocein diacetate.
  • the filter can be stained with Dif Quik® dye (American Scientific Products) and the number of cells migrating can be determined microscopically.
  • the number of cells migrating in the presence of the compound are divided by the number of cells migrating in control wells (without the compound).
  • the quotant is the % inhibition for the compound which can then be plotted using standard graphics techniques against the concentration of compound used.
  • the 50% inhibition point is then determined using a line fit analysis for all concentrations tested.
  • the line fit for all data points must have an coefficient of correlation (R squared) of >90% to be considered a valid assay.
  • compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.
  • the active compounds of the invention may also be formulated for sustained delivery.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinized maize starch, polyinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or sodium
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • the active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • a proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is 0.1 to 1000 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • Aerosol formulations for treatment of the conditions referred to above are preferably arranged so that each metered dose or “puff” of aerosol contains 20 ⁇ g to 1000 ⁇ g of the compound of the invention.
  • the overall daily dose with an aerosol will be within the range 0.1 mg to 1000 mg.
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
  • the active agents can be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in U.S. Pat. Nos. 3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397.
  • the compounds of the invention can also be utilized in combination therapy with other therapeutic agents such as with T-cell immunosuppressant agents such as cyclosporin A and FK-506, with steroid sparing agents such as Cellcept), or with classical anti-inflammatory agents (e.g. cyclooxygenase/lipoxegenase inhibitors) such as tenidap, aspirin, acetaminophen, naproxen and piroxicam.
  • T-cell immunosuppressant agents such as cyclosporin A and FK-506, with steroid sparing agents such as Cellcept
  • classical anti-inflammatory agents e.g. cyclooxygenase/lipoxegenase inhibitors
  • LRMS Low Resolution Mass Spectra
  • LRMS Low Resolution Mass Spectra
  • APCI Atmospheric Pressure Chemical Ionization
  • Room or ambient temperature refers to 20-25° C. All non-aqueous reactions were run under a nitrogen atmosphere for convenience and to maximize yields. Concentration at reduced pressure means that a rotary evaporator was used.
  • the names for the compounds of the invention were created by the Autonom 2.0 PC-batch version from Beilstein Informationssysteme GmbH (ISBN 3-89536-976-4).
  • Method H The product of Method H was converted to the title compound by procedures analogous to those of Methods A and B, from Example 1, except that quinoline-3-carboxylic acid is replaced with quinoxaline-2-carboxylic acid and methylamine is replaced with ammonia gas.
  • Quinoline-3-carboxylic acid 452 1(S)-cyclohexylmethyl-2(S)-hydroxy-6- methyl-4(R)-methylcarbamoyl-hept-6- enyl)-amide 13.
  • Quinoxaline-2-carboxylic acid 453 1(S)-cyclohexylmethyl-2(S)-hydroxy-6- methyl-4(R)-methylcarbamoyl-hept-6- enyl)-amide 14.
  • Quinoline-3-carboxylic acid (5- 170.5-172.5 494 cyclohexyl-1(S)-cyclohexylmethyl-2(S)- hydroxy-4(R)-methylcarbamoyl-pentyl)- amide 22.
  • Quinoline-3-carboxylic acid 1(S)- 454 cyclohexylmethyl-2(S)-hydroxy-6- methyl-4(R)-methylcarbamoyl-heptyl)- amide 23.
  • Quinoline-3-carboxylic acid 476 1(S)-benzyl-2(S)-hydroxy-6-methyl- 4(R)-propylcarbamoyl-heptyl)-amide 33.
  • Trifluoro-methanesulfonic acid 168-170 596 4- ⁇ 3(S)-hydroxy-7-methyl-5(R)- methylcarbamoyl-2(S)-[(quinoline-3- carbonyl)-amino]-octyl ⁇ - phenyl ester 51.
  • Trifluoro-methanesulfonic acid 597 4- ⁇ 3(S)-hydroxy-7-methyl-5(R)- methylcarbamoyl-2(S)-[(quinoxaline- 2-carbonyl)-amino]-octyl ⁇ -phenyl ester 52.
  • Isoquinoline-4-carboxylic acid 220.5-224 494 (5-cyclohexyl-1(S)-cyclohexylmethyl- 2(S)-hydroxy-4(R)-methylcarbamoyl- pentyl)-amide 63.
  • Quinoline-2-carboxylic acid 120-122 488 1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy- 4(R)-methylcarbamoyl-pentyl)-amide 64.
  • Benzofuran-2-carboxylic acid 181-183 437 1(S)-benzyl-2(S)-hydroxy-6-methyl- 4(R)-methylcarbamoyl-heptyl)-amide 75.
  • Quinoline-3-carboxylic acid 188-190 462 1(S)-benzyl-2(S)-hydroxy-7-methyl- 4(R)-methylcarbamoyl-octyl)-amide 77.
  • Benzo[b]thiophene-2-carboxylic acid 179-181 453 1(S)-benzyl-2(S)-hydroxy-6-methyl- 4(R)-methylcarbamoyl-heptyl)-amide 84.
  • 2-Methyl-quinoline-3-carboxylic acid 225-226.5 462 1(S)-benzyl-2(S)-hydroxy-6-methyl- 4(R)-methylcarbamoyl-heptyl)-amide 85.
  • Benzothiazole-2-carboxylic acid 86-89 454 1(S)-benzyl-2(S)-hydroxy-6-methyl- 4(R)-methylcarbamoyl-heptyl)-amide 96.
  • 7,8-Difluoro-quinoline-3-carboxylic acid 179-182 484 1(S)-benzyl-2(S)-hydroxy-6-methyl- 4(R)-methylcarbamoyl-heptyl)-amide 97.
  • Quinoxaline-2-carboxylic acid 125-130 492 1(S)-benzyl-2(S)-hydroxy-7-methyl- 4(R)-propylcarbamoyl-octyl)-amide 112.
  • Quinoxaline-2-carboxylic acid 163-165 463 1(S)-benzyl-4(R)-carbamoyl-2(S)- hydroxy-8-methyl-nonyl)-amide 125.
  • Quinoxaline-2-carboxylic acid 121-123 (2(S)-hydroxy-6-methyl-4(R)- methylcarbamoyl-1(S)-naphthalen-2- ylmethyl-heptyl)-amide 128.
  • Quinoxaline-2-carboxylic acid 185-187 446 1(S)-benzyl-4(R)-carbamoyl-2(S)- hydroxy-7(S)-methyl-nonyl)-amide 139.
  • Quinoxaline-2-carboxylic acid 536 [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7- methyl-4(R)-(piperidine-1-carbonyl)- octyl]-amide 163.
  • Quinoxaline-2-carboxylic acid 537 [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7- methyl-4(R)-(morpholine-4-carbonyl)- octyl]-amide, 164.
  • Quinoxaline-2-carboxylic acid (1(S)- 178-180 461, benzyl-4-carbamoyl-4(S)-cyclohexyl- 444 2(S)-hydroxy-butyl)-amide 170.
  • Quinoxaline-2-carboxylic acid (1(S)- 229-232 447 benzyl-4-carbamoyl-4(S)-cyclohexyl- 2(S)-hydroxy-butyl)-amide 171.
  • Quinoxaline-2-carboxylic acid (1(S)- 126-128 447 benzyl-4-carbamoyl-4(S)-cyclopentyl- 2(S)-hydroxy-butyl)-amide; 172.
  • Quinoxaline-2-carboxylic acid (1(S)- 495 benzyl-4(S)-carbamoyl-2(S)-hydroxy-4- indan-2-yl-butyl)-amide; 181.
  • Quinoxaline-2-carboxylic acid (1(S)- 216-217 474, benzyl-4(S)-carbamoyl-4-cycloheptyl- 457 2(S)-hydroxy-butyl)-amide; 182.
  • Quinoxaline-2-carboxylic acid (1(S)- 477 benzyl-4(S)-carbamoyl-2(S)-hydroxy-5- propyl-octyl)-amide; 183.
  • Quinoxaline-2-carboxylic acid 1(S)- 420 benzyl-4(R)-carbamoyl-2(S)-hydroxy-6- methoxy-hexyl)-amide 208.
  • Quinoxaline-2-carboxylic acid 172-175 450 1(S)-benzyl-4(R)-carbamoyl-7-chloro- 2(S)-hydroxy-oct-6-enyl)-amide 209.
  • Quinoxaline-2-carboxylic acid [4(R)- 206-207 482 carbamoyl-2(S)-hydroxy-4-(1-hydroxy- cyclohexyl)-1(S)-thiophen-2-ylmethyl- butyl]-amide; 269.
  • Quinoxaline-2-carboxylic acid [1(S)- 123-125 495, benzyl-4(S)-carbamoyl-2(S)-hydroxy-4- 379 (4-hydroxy-tetrahydro-thiopyran-4-yl)- butyl]-amide; 270.
  • Quinoxaline-2-carboxylic acid (1(S)- 168-171 benzyl-4(R)-carbamoyl-2(S)-hydroxy-5- o-tolyl-pentyl)-amide 276.
  • Quinoxaline-2-carboxylic acid (1(S)- 190-192 benzyl-2(S)-hydroxy-4(R)- hydroxycarbamoyl-5-phenyl-pentyl)- amide 277.
  • Quinoxaline-2-carboxylic acid [1(S)- 192-195 463, benzyl-4(S)-carbamoyl-2(S)-hydroxy-4- 446 (1-hydroxy-cyclopentyl)-butyl]-amide 278.

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Abstract

Compounds of the formula
Figure US20020198207A1-20021226-C00001
wherein R1, R2, R3, R4, R5 and R6 are as described in the specification are useful to treat inflammation and other immune disorders.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This non-provisional application claims priority from U.S. provisional application No. 60/039,169, filed Feb. 26, 1997 and non-provisional application Ser. No. 09/380,269, filed Feb. 5, 1998.[0001]
    • BACKGROUND OF THE INVENTION
  • The present invention relates to novel hexanoic acid derivatives, methods of use and pharmaceutical compositions containing them. [0002]
  • The compounds of the invention are potent and selective inhibitors of MIP-1α binding to its receptor CCR1 found on inflammatory and immunomodulatory cells (preferably leukocytes and lymphocytes). The CCR1 receptor is also sometimes referred to as the CC-CKR1 receptor. These compounds also inhibit MIP-1α (and the related chemokine shown to interact with CCR1 (e.g., RANTES and MCP-3)) induced chemotaxis of THP-1 cells and human leukocytes and are potentially useful for the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult Respiratory Distress Syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), transplantation tissue rejection (chronic and acute), organ rejection (chronic and acute), atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis). [0003]
  • MIP-1 and RANTES are soluble chemotactic peptides (chemokines) which are produced by inflammatory cells, in particular CD8+ lymphocytes, polymorphonuclear leukocytes (PMNs) and macrophages, [0004] J.Biol. Chem., 270 (30) 29671-29675 (1995). These chemokines act by inducing the migration and activation of key inflammatory and immunomodulatory cells. Elevated levels of chemokines have been found in the synovial fluid of rheumatoid arthritis patients, chronic and rejecting tissue transplant patients and in the nasal secretions of allergic rhinitis patients following allergen exposure (Teran , et al., J. Immunol., 1806-1812 (1996), and Kuna et al., J. Allergy Clin. Immunol. 321 (1994)). Antibodies which interfere with the chemokine/receptor interaction by neutralizing MIP1α or gene disruption have provided direct evidence for the role of MIP-1α and RANTES in disease by limiting the recruitment of monocytes and CD8+ lymphocytes (Smith et al., J. Immunol, 153, 4704 (1994) and Cook et al., Science, 269, 1583 (1995)). Together this data demonstrates that CCR1 antagonists would be an effective at treatment of several immune
  • U.S. Pat. No. 4,923,864, issued May 8, 1990, refers to certain heterocyclic hexanamides that are useful for treating hypertension. [0005]
  • PCT publication WO 89/01488, published Feb. 23, 1989, refers to renin inhibiting peptides which possess nonpeptide linkages. [0006]
  • PCT publication WO 93/025057, published Feb. 4, 1993, refers to dipeptide analogs which are claimed to inhibit retroviral proteases. [0007]
  • PCT publication WO 93/17003, published Sep. 2, 1993, refers to other dipeptide analogs which are claimed to inhibit retroviral proteases. [0008]
  • PCT publication WO 92/17490, published Oct. 15, 1992, refers to peptides containing at least one O-phosphate monoester or diester. The compounds are claimed to possess activity for inhibiting retroviruses. [0009]
  • European Patent Publication 708,085, published Apr. 24, 1996, refers to antiviral ethers of aspartate protease inhibitors. [0010]
    • SUMMARY OF THE INVENTION
  • The present invention relates to compounds of the formula [0011]
    Figure US20020198207A1-20021226-C00002
  • wherein R[0012] 1 is (C2-C9)heteroaryl optionally substituted with one or more substituents (preferably one to three substituents) independently selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C8)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C8)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkyl HN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
  • R[0013] 2 is phenyl-(CH2)m—, naphthyl-(CH2)m—, (C3-C10)cycloalkyl-(CH2)m—, (C1-C6)alkyl or (C2-C9)heteroaryl-(CH2)m—, wherein m is an interger from zero to four, wherein each of said phenyl, naphthyl, (C3-C10)cycloalkyl or (C2-C9)heteroaryl moieties of said phenyl-(CH2)m—, naphthyl-(CH2)m—, (C3-C10)cycloalkyl-(CH2)m— or (C2-C9)heteroaryl-(CH2)m— groups may optionally be substituted with one or more substituents (preferably one to three substituents) independently selected from hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C8)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3-phenyl, phenoxy, benzyloxy, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
  • R[0014] 3 is hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl-(CH2)n—, (C2-C9)heterocycloalkyl-(CH2)n—, (C2-C9)heteroaryl-(CH2)n— or aryl-(CH2)n—; wherein n is an interger from zero to six;
  • wherein said R[0015] 3 (C1-C10)alkyl group may optionally be substituted with one or more substituents, (preferably from one to three substituents) independently selected from hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-N H-(C═O)—, [(C1-C6)al kyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkY]2 N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl; and wherein any of the carbon-carbon single bonds of said (C1-C10)alkyl may optionally be replaced by a carbon-carbon double bond;
  • wherein the (C[0016] 3-C10)cycloalkyl moiety of said R3 (C3-C10)cycloalkyl-(CH2)n— group may optionally be substituted by one to three substitutents independently selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkyl HN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
  • wherein the (C[0017] 2-C9)heterocycloalkyl moiety of said R3 (C2-C9)heterocycloalkyl-(CH2)n— group may contain from one to three heteroatoms independently selected from nitrogen, sulfur, oxygen, >S(═O), >SO2 or >NR6, wherein said (C2-C9)heterocycloalkyl moiety of said (C2-C9)heterocycloalkyl-(CH2)n— group may optionally be substituted on any of the ring carbon atoms capable of forming an additional bond (preferably one to three substitutents per ring) with a substituent independently selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
  • wherein the (C[0018] 2-C9)heteroaryl moiety of said R3 (C2-C9)heteroaryl-(CH2)n— group may contain from one to three heteroatoms independently selected from nitrogen, sulfur or oxygen, wherein said (C2-C9)heteroaryl moiety of said (C2-C9)heteroaryl-(CH2)r— group may optionally be substituted on any of the ring carbon atoms capable of forming an additional bond (preferably one to three substitutents per ring) with a substituent selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3-phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl; and
  • wherein said aryl moiety of said R[0019] 3 aryl-(CH2)n— group is optionally substituted phenyl or naphthyl, wherein said phenyl and naphthyl may optionally be substituted with from one to three substituents independently selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)-(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkyl HN—SO2-(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
  • or R[0020] 3 and the carbon to which it is attached form a five to seven membered carbocyclic ring, wherein any of the carbon atoms of said five membered carbocyclic ring may optionally be substituted with a substituent selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)-(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl; wherein one of the carbon-carbon bonds of said five to seven membered carbocyclic ring may optionally be fused to an optionally substituted phenyl ring, wherein said substitutents may be independently selected from hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-N H-(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)-(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
  • R[0021] 4 is hydrogen, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C═O)—, (C3-C10)cycloalkyl-(CH2)p—, (C2-C9)heterocycloalkyl-(CH2)p—, (C2-C9)heteroaryl-(CH2)p—, phenyl-(CH2)p—, or naphthyl-(CH2)p—, wherein p is an integer from zero to four; wherein said (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl, phenyl and naphthyl groups of said (C2-C9)heterocycloalkyl-(CH2)p—, (C2-C9)heteroaryl-(CH2)p—, phenyl-(CH2)p—, or naphthyl-(CH2)p— may be optionally substituted on any of the ring atoms capable of supporting an additional bond (preferably zero to two substituents per ring) with a substituent selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C8)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6) alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2 amino, amino(C1-C6)alkyl, (C1-C6)alkylamino (C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
  • or R[0022] 4 and R5 together with the nitrogen atom to which they are attached form a (C2-C9)heterocycloalkyl group wherein any of the ring atoms of said (C2-C9)heterocycloalkyl group may optionally be substituted, preferably from zero to two substituents, with a substituent selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6) alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2 amino, amino(C1-C6)alkyl, (C1-C6)alkylamino (C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
  • R[0023] 5 is hydrogen, (C1-C6)alkyl or amino;
  • R[0024] 6 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy-(CH2)g—, (C1-C6)alkoxy(C═O)—(CH2)g—, (C1-C6)alkyl-(SO2)—(CH2)9—, (C6-C10)aryloxy-(CH2)9—, (C6-C10)aryloxy(C═O)—(CH2)9—, or (C1-C10)aryl-(SO2)—(CH2)9—, wherein g is an integer from zero to four;
  • with the proviso that when one of R[0025] 4 or R5 is hydrogen, and the other of R4 or R5 is (C1-C6)alkyl; R2 is (C3-C10)cycloalkyl or isopropyl and R3 is (C3-C5)alkyl, phenyl, methylvinyl, dimethylvinyl, halovinyl, hydroxy(C1-C3)alkyl or amino(C1-C4)alkyl then R1 must be other than indol-5-yl, 6-azaindol-2-yl, 2,3-dichloro-pyrrol-5-yl, 4-hydroxyquinolin-3-yl, 2-hydroxyquinoxalin-3-yl, 6-azaindolin-3-yl, or optionally substituted indol-2 or 3-yl;
  • and the pharmaceutically acceptable salts of such compounds. [0026]
  • The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts. [0027]
  • The invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. [0028]
  • The compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof. [0029]
  • Unless otherwise indicated, the alkyl and alkenyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine, and iodine. [0030]
  • (C[0031] 3-C10)Cycloalkyl when used herein refers to cycloalkyl groups containing zero to two levels of unsaturation such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1 ]octane, norbornanyl etc.
  • (C[0032] 2-C9)Heterocycloalkyl when used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skill in the art will understand that the connection of said (C2-C9)heterocycloalkyl rings is through a carbon or a sp3 hybridized nitrogen heteroatom.
  • (C[0033] 2-C9)Heteroaryl when used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, -benzoxazinyl; etc. One of ordinary skill in the art will understand that the connection of said (C2-C9)heterocycloalkyl rings is through a carbon atom or a s hybridized nitrogen heteroatom.
  • Aryl when used herein refers to phenyl or naphthyl. [0034]
  • The compounds of this invention include all conformational isomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e.g., enantiomers and diastereomers), as well as racemic, diastereomeric and other mixtures of such isomers. [0035]
  • Preferred compounds of the of formula I include those with the stereochemistry depicted in formula [0036]
    Figure US20020198207A1-20021226-C00003
  • Preferred compounds of the formula I include those wherein R[0037] 1 is optionally substituted pyrazolo[3,4-b]pyridinyl, cinnolinyl, pyridinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzothiazolyl, indolyl, pyrazinyl, benzoimidazolyl, benzofuranyl, benzo[b]thiophenyl, naphthalenyl, quinoxalinyl, isoquinolinyl, 5,6,7,8-tetrahydro-quinolin-3-yl or quinolinyl, more preferably pyrazolo[3,4-b]pyridin-5-yl, cinnolin-4-yl, pyridin-2-yl, 6,7-dihydro-5H-[1]pyrindin-3-yl, benzothiazol-2-yl, indol-2-yl, pyrazin-2-yl, benzoimidazol-2-yl, benzofuran-2-yl, benzo[b]thiophen-2-yl, naphthalen-2-yl, quinoxalin-2-yl, quinoxalin-6-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, 5,6,7,8-tetrahydro-quinolin-3-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl, most preferably quinoxalin-6-yl, quinolin-2-yl, quinolin-3-yl, quinoxalin-2-yl, quinolin-4-yl or quinolin-6-yl.
  • Other preferred compounds of formula I include those wherein R[0038] 2 is optionally substituted phenyl, benzyl, naphthyl, cyclohexyl, thienyl, thiazolyl, pyridyl, oxazolyl, furanyl, or thiophenyl; wherein said substituents are independently selected from hydrogen, halo, (C1-C6)alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, —C(═O)—OH, (C1-C6)alkoxy, (C1-C6)alkoxy(C═O)—, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, phenoxy, and benzyloxy.
  • Other preferred compounds of formula I include those wherein R[0039] 3 is optionally substituted (C1-C10)alkyl, benzyl, pyranyl or (C3-C10)cycloalkyl-(CH2)n—, wherein any of the carbon-carbon single bonds of said (C1-C10)alkyl may be optionally replaced by a carbon-carbon double bond; more preferably optionally substituted n-butyl, isobutyl, n-pentyl, 3-methyl-butyl, 2-methyl-pentyl, allyl, cyclopentyl, cyclohexyl or cycloheptyl, more preferably wherein the substituent is fluoro, (C1-C6)alkyl or hydroxy.
  • Examples of specific preferred compounds of the formula I are the following: [0040]
  • 7,8-difluoro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0041]
  • 8-fluoro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0042]
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-7-fluoro-1(S)-(3-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide; [0043]
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(2-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide; [0044]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-4-(2,6-dimethyl-tetrahydro-pyran-4-yl)-2(S)-hydroxy-butyl]-amide; [0045]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)]-amide; [0046]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)]-amide; [0047]
  • quinoxaline-2-carboxylic acid [1(S)-cyclohexylmethyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)]-amide; [0048]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0049]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-(4,4-difluoro-1-hydroxy-cyclohexyl)-2(S)-(hydroxy-4-hydroxycarbamoyl-butyl )]-amide; [0050]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-4(S)-(4,4-difluoro-cyclohexyl)-2(S)-hydroxy-butyl]-amide; [0051]
  • quinoline-3-carboxylic acid (1(S)-benzyl-4(S)-carbamoyl-4-cyclohexyl-2(S)-hydroxy-butyl)-amide; [0052]
  • quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiophen-2-ylmethyl-octyl)-amide; [0053]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-7-chloro-2(S)-hydroxy-oct-6-enyl)]-amide; [0054]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-phenyl-pentyl)]-amide; [0055]
  • N-(1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-5,6-dichloro-nicotinamide; [0056]
  • quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiazol-4-ylmethyl-octyl)-amide; [0057]
  • benzothiazole-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)]-amide; and [0058]
  • benzofuran-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)]-amide. [0059]
  • Examples of other compounds of the formula I are the following: [0060]
  • quinoxaline-2-carboxylic acid (4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-1-thiazol-4-ylmethyl-octyl)-amide; [0061]
  • quinoxaline-2-carboxylic acid (7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-thiazol-4-ylmethyl-octyl)-amide; [0062]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-1-thiazol-4-ylmethyl-butyl]-amide; [0063]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-thiazol-4-ylmethyl-butyl]-amide; [0064]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-thiazol-4-ylmethyl-butyl]-amide; [0065]
  • quinoxaline-2-carboxylic acid [4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-1-thiazol-4-ylmethyl-butyl]-amide; [0066]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-1-(3,5-difluoro-benzyl)-7-fluoro-2-hydroxy-7-methyl-octyl]-amide; [0067]
  • quinoxaline-2-carboxylic acid [1-(3,5-difluoro-benzyl)-7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl]-amide; [0068]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-1-(3,5-difluoro-benzyl)-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0069]
  • quinoxaline-2-carboxylic acid [1-(3,5-difluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0070]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-1-(3,5-difluoro-benzyl)-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-butyl]-amide; [0071]
  • quinoxaline-2-carboxylic acid [1-(3,5-difluoro-benzyl)-4-(4,4-difluoro-cyclohexyl )-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide; [0072]
  • quinoxaline-2-carboxylic acid (4-carbamoyl-2-hydroxy-7-methyl-1-pyridin-2-ylmethyl-octyl)-amide; [0073]
  • quinoxaline-2-carboxylic acid (7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-pyridin-2-ylmethyl-octyl)-amide; [0074]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(2,6-dimethyl-tetrahydro-pyran-4-yl)-2-hydroxy-1-pyridin-2-ylmethyl-butyl]-amide; [0075]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-pyridin-2-ylmethyl-butyl]-amide; [0076]
  • quinoxaline-2-carboxylic acid (4-carbamoyl-4-cyclohexyl-2-hydroxy-1-pyridin-2-ylmethyl-butyl)-amide; [0077]
  • quinoxaline-2-carboxylic acid [4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-1-pyridin-2-ylmethyl-butyl]-amide; [0078]
  • quinoxaline-2-carboxylic acid (4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-1-pyridin-3-ylmethyl-octyl)-amide; [0079]
  • quinoxaline-2-carboxylic acid (2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-pyridin-3-ylmethyl-octyl)-amide; [0080]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-1-pyridin-3-ylmethyl-butyl]-amide; [0081]
  • quinoxaline-2-carboxylic acid [4-(2,6-dimethyl-tetrahydro-pyran-4-yl)-2-hydroxy-4-hydroxycarbamoyl-1-pyridin-3-ylmethyl-butyl]-amide; [0082]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-pyridin-3-ylmethyl-butyl]-amide; [0083]
  • quinoxaline-2-carboxylic acid (4-cyclohexyl-2-hydroxy-4-hydroxycarbamoyl-1-pyridin-3-ylmethyl-butyl)-amide; [0084]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-7-fluoro-1-(4-fluoro-benzyl)-2-hydroxy-7-methyl-octyl]-amide; [0085]
  • quinoxaline-2-carboxylic acid [7-fluoro-1-(4-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl]-amide; [0086]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-1-(4-fluoro-benzyl)-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0087]
  • quinoxaline-2-carboxylic acid [1-(4-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0088]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-1-(4-fluoro-benzyl)-2-hydroxy-butyl]-amide; [0089]
  • quinoxaline-2-carboxylic acid [4-(4,4-difluoro-cyclohexyl)-1-(4-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide; [0090]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-1-(3-fluoro-benzyl)-2-hydroxy-4-(1-hydroxy-cyclohexyl)-butyl]-amide; [0091]
  • quinoxaline-2-carboxylic acid [7-fluoro-1-(3-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl]-amide; [0092]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(2,6-dimethyl-tetrahydro-pyran-4-yl)-1-(3-fluoro-benzyl)-2-hydroxy-butyl]-amide; [0093]
  • quinoxaline-2-carboxylic acid [1-(3-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0094]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-1-(3-fluoro-benzyl)-2-hydroxy-butyl]-amide; [0095]
  • quinoxaline-2-carboxylic acid [4-cyclohexyl-1-(3-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide; [0096]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-1-(2-fluoro-benzyl)-2-hydroxy-4-(1-hydroxy-cyclohexyl)-butyl]-amide; [0097]
  • quinoxaline-2-carboxylic acid [7-fluoro-1-(2-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl]-amide; [0098]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(2,6-dimethyl-tetrahydro-pyran-4-yl)-1-(2-fluoro-benzyl)-2-hydroxy-butyl]-amide; [0099]
  • quinoxaline-2-carboxylic acid [1-(2-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0100]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-1-(2-fluoro-benzyl)-2-hydroxy-butyl]-amide; [0101]
  • quinoxaline-2-carboxylic acid [4-cyclohexyl-1-(2-fluoro-benzyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide; [0102]
  • quinoxaline-2-carboxylic acid (4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-1-thiophen-2-ylmethyl-octyl)-amide; [0103]
  • quinoxaline-2-carboxylic acid (7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-thiophen-2-ylmethyl-octyl)-amide; [0104]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-1-thiophen-2-ylmethyl-butyl]-amide; [0105]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-thiophen-2-ylmethyl-butyl]-amide; [0106]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-thiophen-2-ylmethyl-butyl]-amide; [0107]
  • quinoxaline-2-carboxylic acid [4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-1-thiophen-2-ylmethyl-butyl]-amide; [0108]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-2-hydroxy-7-methyl-1-(3-trifluoromethyl-benzyl)-octyl]-amide; [0109]
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-(3-trifluoromethyl-benzyl)-octyl]-amide; [0110]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-carbamoyl-4-(4-hydroxy-2,6-dimethyl-tetrahydro-pyran-4-yl)-1-(3-trifluoromethyl-benzyl)-butyl]-amide; [0111]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-(3-trifluoromethyl-benzyl)-butyl]-amide; [0112]
  • quinoxaline-2-carboxylic acid {4-carbamoyl-4-cyclohexyl)-2-hydroxy-1-(3-trifluoromethyl-benzyl)-butyl}-amide; [0113]
  • quinoxaline-2-carboxylic acid {4-hydroxycarbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-(3-trifluoromethyl-benzyl)-butyl}-amide; [0114]
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-carbamoyl-7-methyl-1-(3-trifluoromethoxy-benzyl)-octyl]-amide; [0115]
  • quinoxaline-2-carboxylic acid [4-hydroxycarbamoyl-2-hydroxy-7-methyl-1-(3-trifluoromethoxy-benzyl)-octyl]-amide; [0116]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-carbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-(3-trifluoromethoxy-benzyl)-butyl]-amide; [0117]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(4-hydroxy-2,6-dimethyl-tetrahydro-pyran-4-yl)-1-(3-trifluoromethoxy-benzyl)-butyl]-amide; [0118]
  • quinoxaline-2-carboxylic acid {4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-(3-trifluoromethoxy-benzyl)-butyl}-amide; [0119]
  • quinoxaline-2-carboxylic acid {4-hydroxycarbamoyl-4-cyclohexyl)-2-hydroxy-1-(3-trifluoromethoxy-benzyl)-butyl}-amide; [0120]
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-carbamoyl-7-methyl-1-(4-trifluoromethoxy-benzyl)-octyl]-amide; [0121]
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-(4-trifluoromethoxy-benzyl)-octyl]-amide; [0122]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-carbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-(4-trifluoromethoxy-benzyl)-butyl]-amide; [0123]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-(4-trifluoromethoxy-benzyl)-butyl]-amide; [0124]
  • quinoxaline-2-carboxylic acid {4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-(4-trifluoromethoxy-benzyl)-butyl}-amide; [0125]
  • quinoxaline-2-carboxylic acid {4-hydroxycarbamoyl-4-(4,4-difluoro-cyclohexyl )-2-hydroxy-1-(4-trifluoromethoxy-benzyl)-butyl}-amide; [0126]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-2-hydroxy-7-methyl-1-(2-trifluoromethyl-benzyl)-octyl]-amide; [0127]
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-(2-trifluoromethoxy-benzyl)-octyl]-amide; [0128]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-carbamoyl-4-(4-hydroxy-2,6-dimethyl-tetrahydro-pyran-4-yl)-1-(2-trifluoromethoxy-benzyl)-butyl]-amide; [0129]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-(2-trifluoromethoxy-benzyl)-butyl]-amide; [0130]
  • quinoxaline-2-carboxylic acid {4-carbamoyl-4-cyclohexyl)-2-hydroxy-1-(2-trifluoromethoxy-benzyl)-butyl}-amide; [0131]
  • quinoxaline-2-carboxylic acid {4-hydroxycarbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-(2-trifluoromethoxy-benzyl)-butyl}-amide; [0132]
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-carbamoyl-7-methyl-1-[3-(1-hydroxy-1-methyl-ethyl)-benzyl]-octyl]-amide; [0133]
  • quinoxaline-2-carboxylic acid [4-hydroxycarbamoyl-2-hydroxy-7-methyl -1-[3-(1-hydroxy-1-methyl-ethyl)-benzyl]-octyl]-amide; [0134]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-carbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-[3-(1-hydroxy-1-methyl-ethyl)-benzyl]-butyl]-amide; [0135]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(4-hydroxy-2,6-dimethyl-tetrahyd ro-pyran-4-yl)-1-3-(1-hydroxy-1-methyl-ethyl)-benzyl)-butyl]-amide; [0136]
  • quinoxaline-2-carboxylic acid {4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-[3-(1-hydroxy-1-methyl-ethyl)-benzyl]-butyl}-amide; [0137]
  • quinoxaline-2-carboxylic acid {4-hydroxycarbamoyl-4-(cyclohexyl)-2-hydroxy-1-[3-(1-hydroxy-1-methyl-ethyl)-benzyl]-butyl}-amide; [0138]
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-carbamoyl-7-methyl-1-thiophen-3-ylmethyl-butyl]-amide; [0139]
  • quinoxaline-2-carboxylic acid [7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-thiophen-3-ylmethyl-butyl]-amide; [0140]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-carbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-thiophen-3-ylmethyl-butyl]-amide; [0141]
  • quinoxaline-2-carboxylic acid [2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-1-thiophen-3-ylmethyl-butyl]-amide; [0142]
  • quinoxaline-2-carboxylic acid [4-carbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-thiophen-3-ylmethyl-butyl]-amide; [0143]
  • quinoxaline-2-carboxylic acid [4-hydroxycarbamoyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-1-thiophen-3-ylmethyl-butyl]-amide; [0144]
  • [[1,8]naphthyridine-3-carboxylic acid (1-benzyl-4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide; [0145]
  • [1,8]naphthyridine-3-carboxylic acid (1-benzyl-7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl)-amide; [0146]
  • [1,8]naphthyridine-3-carboxylic acid [1-benzyl-4-carbamoyl-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0147]
  • [1,8]naphthyridine-3-carboxylic acid [1-benzyl-2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0148]
  • [1,5] naphthyridine-3-carboxylic acid (1-benzyl-4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide; [0149]
  • [1,5]naphthyridine-3-carboxylic acid (1-benzyl-7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl)-amide; [0150]
  • [1,5]naphthyridine-3-carboxylic acid [1-benzyl-4-carbamoyl-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0151]
  • [1,5]naphthyridine-3-carboxylic acid [1-benzyl-2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0152]
  • [1,8] naphthyridine-2-carboxylic acid (1-benzyl-4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide; [0153]
  • [1,8]naphthyridine-2-carboxylic acid (1-benzyl-7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl)-amide; [0154]
  • [1,8]naphthyridine-2-carboxylic acid [1-benzyl-4-carbamoyl-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0155]
  • [1,8]naphthyridine-2-carboxylic acid [1-benzyl-2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0156]
  • [1,6] naphthyridine-2-carboxylic acid (1-benzyl-4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide; [0157]
  • [1,6]naphthyridine-2-carboxylic acid (1-benzyl-7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl)-amide; [0158]
  • [1,6]naphthyridine-2-carboxylic acid [1-benzyl-4-carbamoyl-2-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0159]
  • [1,6]naphthyridine-2-carboxylic acid [1-benzyl-2-hydroxy-4-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0160]
  • quinoline-3-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0161]
  • quinoxaline-2-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0162]
  • quinoxaline-2-carboxylic acid (6-chloro-1(S)-cyclohexyl methyl-2(S)-hydroxy-4(S)-methylcarbamoyl-hept-6-enyl)-amide; [0163]
  • quinoline-3-carboxylic acid (2(S)-hydroxy-1(S)-isobutyl-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0164]
  • quinoxaline-2-carboxylic acid 1(S)-sec-butyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0165]
  • quinoline-3-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-hept-6-enyl)-amide; [0166]
  • quinoxaline-2-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-hept-6-enyl)-amide; [0167]
  • N-1(S)-cyclohexylmethyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-5-phenyl-nicotinamide; [0168]
  • quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0169]
  • quinoxaline-2-carboxylic acid 1(S)-cyclohexylmethyl-4(R)-dimethylcarbamoyl-2(S)-hydroxy-6-methyl-hept-6-enyl)-amide; [0170]
  • quinoline-3-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0171]
  • quinoxaline-2-carboxylic acid 1(S)-cyclohexyl methyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0172]
  • isoquinoline-4(R)-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0173]
  • quinoline-3-carboxylic acid (4(R)-carbamoyl-1(S)-cyclohexylmethyl-2(S)-hydroxy-6-methyl-heptyl)-amide; [0174]
  • quinoline-3-carboxylic acid (5-cyclohexyl-1(S)-cyclohexylmethyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide; [0175]
  • quinoline-3-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0176]
  • quinoline-3-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-6-methyl-4(S)-methylcarbamoyl-heptyl)-amide; [0177]
  • quinoline-3-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-4(R)-methylcarbamoyl-5-phenyl-pentyl)-amide; [0178]
  • quinoxaline-2-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-4(R)-methylcarbamoyl-5-phenyl-pentyl)-amide; [0179]
  • quinoline-3-carboxylic acid 1(S)-benzyl-4(R)-butylcarbamoyl-2(S)-hydroxy-6-methyl-heptyl)-amide; [0180]
  • quinoline-3-carboxylic acid 1(S)-benzyl-4(R)-cyclobutylcarbamoyl-2(S)-hydroxy-6-methyl-heptyl)-amide; [0181]
  • quinoline-3-carboxylic acid 1(S)-benzyl-4(R)-benzylcarbamoyl-2(S)-hydroxy-6-methyl-heptyl)-amide; [0182]
  • quinoline-3-carboxylic acid 1(S)-benzyl-4(R)-cyclopropylcarbamoyl-2(S)-hydroxy-6-methyl-heptyl)-amide; [0183]
  • quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(S)-methylcarbamoyl-heptyl)-amide; [0184]
  • quinoline-3-carboxylic acid 1(S)-benzyl-4(R)-ethylcarbamoyl-2(S)-hydroxy-6-methyl-heptyl)-amide; [0185]
  • quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-propylcarbamoyl-heptyl)-amide; [0186]
  • quinoline-3-carboxylic acid [1-benzyl-2(S)-hydroxy-4(R)-(2(S)-hydroxy-ethylcarbamoyl)-6-methyl-heptyl]-amide; [0187]
  • cinnoline-4(R)-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0188]
  • isoquinoline-4(R)-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0189]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0190]
  • N-1(S)-Benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-5-bromo-nicotinamide; [0191]
  • quinoline-3-carboxylic acid 1(R)-cyclohexylmethyl-2(R)-hydroxy-6-methyl-4(S)-methylcarbamoyl-heptyl)-amide; [0192]
  • quinoxaline-2-carboxylic acid [1-(4-benzyloxy-benzyl)-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide; [0193]
  • quinoline-3-carboxylic acid [1-(4-benzyloxy-benzyl)-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide; [0194]
  • isoquinoline-1-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0195]
  • quinoline-4(R)-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0196]
  • quinoline-6-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0197]
  • quinoline-3-carboxylic acid [2(S)-hydroxy-1-(4-hydroxy-benzyl)-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide; [0198]
  • quinoline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0199]
  • naphthalene-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0200]
  • quinoline-3-carboxylic acid 1(S)-benzyl-5-cyclohex-1-enyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide; [0201]
  • quinoline-3-carboxylic acid [1-benzyl-2(S)-hydroxy-6-methyl-4(R)-(3-methyl-butylcarbamoyl)-heptyl]-amide; [0202]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(S)-methylcarbamoyl-heptyl)-amide; [0203]
  • trifluoro-methanesulfonic acid 4-{3(S)-hydroxy-7-methyl-5(R)-methylcarbamoyl-2(S)-[(quinoline-3-carbonyl)-amino]-octyl}-phenyl ester; [0204]
  • trifluoro-methanesulfonic acid 4-{3(S)-hydroxy-7-methyl-5(R)-methylcarbamoyl-2(S)-[(quinoxaline-2-carbonyl)-amino]-octyl}-phenyl ester; [0205]
  • quinoline-3-carboxylic acid 1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide; [0206]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide; [0207]
  • isoquinoline-3-carboxylic acid 1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide; [0208]
  • N-1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-5-bromo-nicotinamide; [0209]
  • quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-prop-2-ynylcarbamoyl-heptyl)-amide; [0210]
  • quinoline-3-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-4(R)-hydroxycarbamoyl-6-methyl-heptyl)-amide; [0211]
  • quinoline-3-carboxylic acid 2(S)-hydroxy-1(S)-(4-methoxy-benzyl)-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide; [0212]
  • isoquinoline-3-carboxylic acid (5-cyclohexyl-1(S)-cyclohexylmethyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide; [0213]
  • 5-bromo-N-(5-cyclohexyl-1(S)-cyclohexylmethyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-nicotinamide; [0214]
  • quinoxaline-2-carboxylic acid [2(S)-hydroxy-1(S)-(4-methoxy-benzyl)-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide; [0215]
  • isoquinoline-4(R)-carboxylic acid (5-cyclohexyl-1(S)-cyclohexylmethyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide; [0216]
  • quinoline-2-carboxylic acid 1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide; [0217]
  • isoquinoline-4(R)-carboxylic acid 1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide; [0218]
  • quinoxaline-2-carboxylic acid [2(S)-hydroxy-1(S)-(4-hydroxy-benzyl)-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide; [0219]
  • quinoxaline-2-carboxylic acid (5-cyclohexyl-1(S)-cyclohexylmethyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide; [0220]
  • quinoline-3-carboxylic acid [1(S)-(4-chloro-benzyl)-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide; [0221]
  • quinoxaline-2-carboxylic acid [1(S)-(4-chloro-benzyl)-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide; [0222]
  • quinoline-3-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0223]
  • quinoxaline-2-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0224]
  • quinoline-3-carboxylic acid [1(S)-(4-chloro-benzyl)-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl]-amide; [0225]
  • quinoxaline-2-carboxylic acid [1(S)-(4-chloro-benzyl)-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl]-amide; [0226]
  • quinoline-2-carboxylic acid [1(S)-(4-chloro-benzyl)-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl]-amide; [0227]
  • benzofuran-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0228]
  • N-1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-5,6-dichloro-nicotinamide; [0229]
  • quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0230]
  • N-1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-5-bromo-nicotinamide; [0231]
  • 5,6,7,8-tetrahydro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0232]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0233]
  • quinoline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0234]
  • isoquinoline-4(R)-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0235]
  • quinoxaline-2-carboxylic acid [1-(3,4-dichloro-benzyl)-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide; [0236]
  • benzo[b]thiophene-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl )-amide; [0237]
  • 2-methyl-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0238]
  • 6,7-dimethoxy-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0239]
  • 6,7-difluoro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0240]
  • 1H-benzoimidazole-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0241]
  • 5-methyl-pyrazine-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0242]
  • quinoline-3-carboxylic acid [1(S)-(4-fluoro-benzyl)-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide; [0243]
  • quinoxaline-2-carboxylic acid [1(S)-(4-fluoro-benzyl)-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide; [0244]
  • 5-chloro-1H-indole-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0245]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-7-methyl-octyl)-amide; [0246]
  • 2-methoxy-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcabamoyl-heptyl)-amide; [0247]
  • 5,6-dichloro-1H-benzoimidazole-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0248]
  • benzothiazole-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0249]
  • 7,8-difluoro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0250]
  • 6 7,8-trifluoro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0251]
  • 5,8-dimethyl-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0252]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-butylcarbamoyl-2(S)-hydroxy-7-methyl-octyl)-amide; [0253]
  • quinoline-3-carboxylic acid [1(S)-(3,4-dichloro-benzyl)-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide; [0254]
  • 5,6,7,8-tetrahydro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0255]
  • quinoline-3-carboxylic acid 1(S)-benzyl-5-cyclopentyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide; [0256]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-5-cyclopentyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide; [0257]
  • N-1(S)-benzyl-5-cyclopentyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-5-bromo-nicotinamide; [0258]
  • 5,6,7,8-tetrahydro-quinoline-3-carboxylic acid 1(S)-benzyl-5-cyclopentyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide; [0259]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-5-cyclopentyl-2(S)-hydroxy-pentyl)-amide; [0260]
  • 6,7-dihydro-5H-[1 ]pyrindine-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0261]
  • quinoxaline-2-carboxylic acid [1(S)-(4,4-difluoro-cyclohexylmethyl)-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl]-amide; [0262]
  • quinoxaline-2-carboxylic acid [1(S)-(4,4-difluoro-cyclohexylmethyl)-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl]-amide; [0263]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-ethylcarbamoyl-2(S)-hydroxy-7-methyl-octyl)-amide; [0264]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-propylcarbamoyl-octyl)-amide; [0265]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-cyclopropylcarbamoyl-2(S)-hydroxy-7-methyl-octyl)-amide; [0266]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-cyclobutylcarbamoyl-2(S)-hydroxy-7-methyl-octyl)-amide; [0267]
  • quinoxaline-2-carboxylic acid [1(S)-(4-difluoromethoxy-benzyl)-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl]-amide; [0268]
  • 4-{3(S)-hydroxy-7-methyl-5(R)-methylcarbamoyl-2(S)-[(quinoxaline-2-carbonyl)-amino]-octyl}-benzoic acid methyl ester; [0269]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-butyl)-amide; [0270]
  • 6,7,8-trifluoro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0271]
  • 6,7,8-trifluoro-quinoline-3-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-7-methyl-octyl)-amide; [0272]
  • 6,8-difluoro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0273]
  • 6,8-difluoro-quinoline-3-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-7-methyl-octyl)-amide; [0274]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-butylcarbamoyl-5-cyclopentyl-2(S)-hydroxy-pentyl)-amide; [0275]
  • 6-methyl-pyridine-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl)-amide; [0276]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-8-methyl-4(R)-methylcarbamoyl-nonyl)-amide; [0277]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-8-methyl-nonyl)-amide; [0278]
  • quinoxaline-2-carboxylic acid 1(S)-biphenyl-4(R)-ylmethyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0279]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-7-methyl-oct-6-enyl)-amide; [0280]
  • quinoxaline-2-carboxylic acid (2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-1(S)-naphthalen-2-ylmethyl-heptyl)-amide; [0281]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-7,7-dimethyl-octyl)-amide; [0282]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7,7-dimethyl-4(R)-methylcarbamoyl-octyl)-amide; [0283]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-phenyl-pentyl)-amide; [0284]
  • quinoxaline-2-carboxylic acid 1(S)-biphenyl-4(R)-ylmethyl-4(R)-carbamoyl-2(S)-hydroxy-7-methyl-octyl)-amide; [0285]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-5-(4,4-difluoro-cyclohexyl)-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl]-amide; [0286]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-5-(4,4-difluoro-cyclohexyl)-2(S)-hydroxy-pentyl]-amide; [0287]
  • quinoxaline-2-carboxylic acid [1(S)-(3-fluoro-benzyl)-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl]-amide; [0288]
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide; [0289]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-oct-6-enyl)-amide; [0290]
  • 6,7,8-trifluoro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-nonyl)-amide; [0291]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-7-methyl-nonyl)-amide; [0292]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0293]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0294]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-nonyl)-amide; [0295]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-dimethylcarbamoyl-2(S)-hydroxy-7-methyl-octyl)-amide; [0296]
  • 7,8-difluoro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-4(R)-methylcarbamoyl-5-phenyl-pentyl)-amide; [0297]
  • 7,8-difluoro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0298]
  • 8-fluoro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide; [0299]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-4(R)-methylcarbamoyl-non-6-enyl)-amide; [0300]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-non-6-enyl)-amide; [0301]
  • 7,8 difluoro-quinoline-3-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-7-methyl-octyl )-amide; [0302]
  • 8-fluoro-quinoline-3-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-7-methyl-octyl)-amide; [0303]
  • 4(S)hydroxy-2(R)-(3-methyl-butyl)-6-phenyl-5(S)-[(quinoxaline-2(R)-carbonyl)-amino]-hexanoic acid; [0304]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-nonyl)-amide; [0305]
  • 2-{2(S)-hydroxy-4-phenyl-3(S)-[(quinoxaline-2-carbonyl)-amino]-butyl}-N1, N4-dimethyl-succinamide; [0306]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4-ethylcarbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0307]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-butylcarbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0308]
  • quinoxaline-2-carboxylic acid [7-fluoro-1(S)-(4-fluoro-benzyl)-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl]-amide; [0309]
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3,4-dichloro-benzyl)-7-fluoro-2(S)-hydroxy-7-methyl-octyl]-amide; [0310]
  • 7,8-difluoro-quinoline-3-carboxylic acid [4(R)-carbamoyl-1(S)-(3,4-dichloro-benzyl)-7-fluoro-2(S)-hydroxy-7-methyl-octyl]-amide; [0311]
  • quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-phenethyl-octyl)-amide; [0312]
  • 7,8-difluoro-quinoline-3-carboxylic acid [4(R)-carbamoyl-7-fluoro-1(S)-(4-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide; [0313]
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-7-fluoro-1(S)-(4-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide; [0314]
  • quinoxaline-2-carboxylic acid {1(S)-[4(R)-(3-methyl-butyl)-5-oxo-tetrahydro-furan-2-yl]-2(S)-phenyl-ethyl}-amide; [0315]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(4-methyl-piperazine-1-carbonyl)-octyl]-amide; [0316]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-(tetrahydro-pyran-4(R)-yl)-pentyl]-amide; [0317]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(piperidine-1-carbonyl)-octyl]-amide; [0318]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(morpholine-4(R)-carbonyl )-octyl]-amide; [0319]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(3-morpholin-4-yl-propionyl)-octyl]-amide; [0320]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-3-(2-carbamoyl-indan-2-yl)-2(S)-hydroxy-propyl]-amide; [0321]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-4(R)-methylcarbamoyl-7-phenyl-hept-6-enyl)-amide; [0322]
  • quinoline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0323]
  • 6,7-dihydro-5H-[1 ]pyrindine-3-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0324]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-4-carbamoyl-4(S)-cyclohexyl-2(S)-hydroxy-butyl)-amide; [0325]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-4-carbamoyl-4(S)-cyclohexyl-2(S)-hydroxy-butyl)-amide; [0326]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-4-carbamoyl-4(S)-cyclohexyl-2(S)-hydroxy-butyl)-amide; [0327]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-4-carbamoyl-4(S)-cyclopentyl-2(S)-hydroxy-butyl)-amide; [0328]
  • quinoline-3-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0329]
  • N-1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-5-bromo-nicotinamide; [0330]
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1-(2(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide; [0331]
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-I (S)-(2(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide; [0332]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-4(S)-(4-isopropyl-cyclohexyl)-butyl]-amide; [0333]
  • quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiophen-2-ylmethyl-octyl)-amide; [0334]
  • quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiazol-4(R)-ylmethyl-octyl)-amide; [0335]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4(S)-(3,3,5,5-tetramethyl-cyclohexyl)-butyl]-amide; [0336]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4(S)-indan-2-yl-butyl)-amide; [0337]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-4(S)-carbamoyl-4(S)-cycloheptyl-2(S)-hydroxy-butyl)-amide; [0338]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-propyl-octyl)-amide; [0339]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-propyl-oct-5-enyl)-amide; [0340]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2,7-dihydroxy-7-methyl-octyl)-amide; [0341]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-7-chloro-2(S)-hydroxy-4(R)-methylcarbamoyl-hept-6-enyl)-amide; [0342]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-7-chloro-2(S)-hydroxy-4(R)-methylcarbamoyl-hept-6-enyl)-amide; [0343]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-6-chloro-2(S)-hydroxy-4(S)-methylcarbamoyl-hept-6-enyl)-amide; [0344]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-6-chloro-2(S)-hydroxy-hept-6-enyl)-amide; [0345]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-6-cyclopropyl-2(S)-hydroxy-hexyl)-amide; [0346]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-6-cyclopropyl-2(S)-hydroxy-4(R)-methylcarbamoyl-hexyl)-amide; [0347]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-4(S)-(4-methyl-cyclohexyl)-butyl]-amide; [0348]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-4(S)-indan-2-yl-butyl)-amide; [0349]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-(4-trifluoromethoxy-phenyl)-pentyl]-amide; [0350]
  • quinoxaline-2-carboxylic acid [1-benzyl-4(R)-carbamoyl-5-(4-fluoro-phenyl)-2(S)-hydroxy-pentyl]-amide; [0351]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-chloro-2(S)-hydroxy-hept-6-enyl)-amide; [0352]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-chloro-2(S)-hydroxy-hept-6-enyl)-amide; [0353]
  • 3-Hydroxy-quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0354]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-benzylcarbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0355]
  • quinoxaline-2-carboxylic acid {1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-[(pyridin-3-ylmethyl)-carbamoyl]-octyl}-amide; [0356]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-8,8-trifluoro-2(S)-hydroxy-4(R)-methylcarbamoyl-7-trifluoromethyl-octyl)-amide; quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-8,8-trifluoro-2(S)-hydroxy-7-trifluoromethyl-octyl)-amide; [0357]
  • quinoxaline-2-carboxylic acid [2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-1(S)-(4-methylcarbamoyl-benzyl)-octyl]-amide; [0358]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-4(R)-carbamoyl-5-ethyl-2(S)-hydroxy-heptyl)-amide; [0359]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4(S)-(tetrahydro-pyran-4-yl)-butyl]-amide; [0360]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(2(R)-pyridin-2-yl-ethylcarbamoyl )-octyl]-amide; quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-(3,4-dimethoxy-benzylcarbamoyl)-7-fluoro-2(S)-hydroxy-7-methyl-octyl]-amide; [0361]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-6-methoxy-hexyl)-amide; [0362]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-chloro-2(S)-hydroxy-oct-6-enyl)-amide; [0363]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-7-chloro-2(S)-hydroxy-4(R)-methylcarbamoyl-oct-6-enyl)-amide; [0364]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-4(S)-(3,5-dimethyl-cyclohexyl)-2(S)-hydroxy-butyl]-amide; quinoxaline-2-carboxylic acid {1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-[(pyridin-2-ylmethyl)-carbamoyl]-octyl}-amide; [0365]
  • quinoxaline-2-carboxylic acid {1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-[2-(4-hydroxy-phenyl)-ethylcarbamoyl]-7-methyl-octyl}-amide; [0366]
  • quinoxaline-2-carboxylic acid {1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-[(thiophen-2-ylmethyl)-carbamoyl]-octyl}-amide; [0367]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-6-phenoxy-hexyl)-amide; [0368]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-6-isopropoxy-hexyl)-amide; quinoxaline-2-carboxylic acid {1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-[2-(4-sulfamoyl-phenyl)-ethylcarbamoyl]-octyl}-amide; [0369]
  • quinoxaline-2-carboxylic acid {1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-[(pyridin-4-ylmethyl)-carbamoyl]-octyl}-amide; [0370]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4-(2-ethylsulfanyl-ethylcarbamoyl)-7-fluoro-2(S)-hydroxy-7-methyl-octyl]-amide; [0371]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-(2-methoxy-ethylcarbamoyl)-7-methyl-octyl]-amide; [0372]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(2-pyridin-3-yl-ethylcarbamoyl)-octyl]-amide; [0373]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(2-pyridin-4(R)-yl-ethylcarbamoyl)-octyl]-amide; [0374]
  • quinoxaline-6-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0375]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-6-tert-butoxy-4(R)-carbamoyl-2(S)-hydroxy-hexyl)-amide; [0376]
  • quinoxaline-2-carboxylic acid {1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-[2-1(S)-methyl-1H-pyrrol-2-yl)-ethylcarbamoyl]-octyl}-amide; [0377]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-4-(1,1-dioxo-hexahydro-thiopyran-4-yl)-2(S)-hydroxy-butyl]-amide; [0378]
  • quinoxaline-2-carboxylic acid {1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-[2-(6-methoxy-1H-indol-3-yl)-ethylcarbamoyl]-7-methyl-octyl}-amide; [0379]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-(2-methoxy-benzylcarbamoyl)-7-methyl-octyl]-amide; [0380]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-(3-methoxy-benzylcarbamoyl)-7-methyl-octyl]-amide; [0381]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-(2-thiophen-2-yl-ethylcarbamoyl)-octyl]-amide; [0382]
  • quinoxaline-2-carboxylic acid {1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-[2-(1H-indol-3-yl)-ethylcarbamoyl]-7-methyl-octyl}-amide; [0383]
  • quinoxaline-2-carboxylic acid {4(R)-[2-(4-amino-phenyl)-ethylcarbamoyl]-1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl}-amide; [0384]
  • quinoxaline-2-carboxylic acid {1(S)-benzyl-4(R)-[2-(3,5-dimethoxy-phenyl)-ethylcarbamoyl]-7-fluoro-2(S)-hydroxy-7-methyl-octyl}-amide; [0385]
  • quinoxaline-2-carboxylic acid {1(S)-benzyl-4(R)-[2-(3,4-dimethoxy-phenyl)-ethylcarbamoyl]-7-fluoro-2(S)-hydroxy-7-methyl-octyl}-amide; [0386]
  • quinoxaline-2-carboxylic acid {1(S)-benzyl-7-fluoro-4(R)-[(furan-2-ylmethyl)-carbamoyl]-2(S)-hydroxy-7-methyl-octyl}-amide; [0387]
  • quinoxaline-2-carboxylic acid {1(S)-benzyl-4(R)-[2-(2,5-dimethoxy-phenyl)-ethylcarbamoyl]-7-fluoro-2(S)-hydroxy-7-methyl-octyl}-amide; [0388]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-(4-methoxy-benzylcarbamoyl)-7-methyl-octyl]-amide; [0389]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-6-cyclohexyloxy-2(S)-hydroxy-hexyl)-amide; [0390]
  • quinoxaline-2-carboxylic acid {4(R)-[(1H-benzoimidazol-2-ylmethyl)-carbamoyl]-1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl}-amide; [0391]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-(2(S)-hydroxymethyl-pyrrolidine-1-carbonyl)-7-methyl-octyl]-amide; [0392]
  • quinoxaline-2-carboxylic acid {1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-[(tetrahydrofuran-2-ylmethyl)-carbamoyl]-octyl}-amide; [0393]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4-carbamoyl-4(S)-(4,4-difluoro-cyclohexyl)-2(S)-hydroxy-butyl]-amide; [0394]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-(2,3-dimethoxy-benzylcarbamoyl)-7-fluoro-2(S)-hydroxy-7-methyl-octyl]-amide; [0395]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-cyclohexyl)-butyl]-amide; [0396]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-4-(2,6-dimethyl-tetrahydro-pyran-4-yl)-2(S)-hydroxy-butyl]-amide; [0397]
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-7-fluoro-1(S)-(3-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide; [0398]
  • 7,8-difluoro-quinoline-3-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0399]
  • N-1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-5,6-dichloro-nicotinamide; [0400]
  • benzofuran-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0401]
  • cinnoline-4(R)-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0402]
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-1-(4-iodo-benzyl)-7-methyl-octyl]-amide; [0403]
  • pyrazine-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0404]
  • 6,7,8-trifluoro-quinoline-3-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0405]
  • quinoline-6-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0406]
  • isoquinoline-3-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0407]
  • 2-methoxy-quinoline-3-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0408]
  • 1H-benzoimidazole-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0409]
  • benzothiazole-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0410]
  • 5-methyl-pyrazine-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0411]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-pyridin-3-yl-pentyl)-amide; [0412]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-cyclohexyl)-butyl]-amide; [0413]
  • quinoline-3-carboxylic acid (1(S)-benzyl-4(S)-carbamoyl-4-cyclohexyl-2(S)-hydroxy-butyl)-amide; [0414]
  • quinoline-2-carboxylic acid (1(S)-benzyl-4(S)-carbamoyl-4-cyclohexyl-2(S)-hydroxy-butyl)-amide; [0415]
  • fluoro-quinoline-3-carboxylic acid (1(S)-benzyl-4(S)-carbamoyl-4-cyclohexyl-2(S)-hydroxy-butyl)-amide; [0416]
  • N-(1(S)-benzyl-4(S)-carbamoyl-4-cyclohexyl-2(S)-hydroxy-butyl)-5,6-dichloro-nicotinamide; [0417]
  • N-(1(S)-benzyl-4(S)-carbamoyl-4-cyclohexyl-2(S)-hydroxy-butyl)-5-bromo-nicotinamide; [0418]
  • quinoxaline-2-carboxylic acid (4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-1-phenyl-octyl)-amide; [0419]
  • quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-pyridin-2-yl-pentyl)-amide; [0420]
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-cyclohexyl)-1(S)-thiophen-2-ylmethyl-butyl]-amide; [0421]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(4-hydroxy-tetrahydro-thiopyran-4-yl)-butyl]-amide; [0422]
  • 1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; [0423]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl)-amide; [0424]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-methoxycarbamoyl-7-methyl-octyl)-amide; [0425]
  • 7,8-difluoro-quinoline-3-carboxylic acid (1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-phenyl-pentyl)-amide; [0426]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-5-(2-chloro-phenyl)-2(S)-hydroxy-pentyl]-amide; [0427]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-o-tolyl-pentyl)-amide; [0428]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-2(S)-hydroxy-4(R)-hydroxycarbamoyl-5-phenyl-pentyl)-amide; [0429]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-cyclopentyl)-butyl]-amide; [0430]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0431]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-5-(3,4-dichloro-phenyl)-2(S)-hydroxy-pentyl]-amide; [0432]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-5-(2-fluoro-phenyl)-2(S)-hydroxy-pentyl]-amide; [0433]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-cyclopentyl)-butyi]-amide; [0434]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-3-methyl-cyclopentyl)-butyl]-amide; [0435]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide; [0436]
  • N-(1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-phenyl-pentyl)-5-bromo-nicotinamide; [0437]
  • 8-Fluoro-quinoline-3-carboxylic acid (1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-phenyl-pentyl)-amide; [0438]
  • 6,7-dihydro-5H-[1 ]pyrindine-3-carboxylic acid (1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-phenyl-pentyl)-amide; [0439]
  • quinoline-3-carboxylic acid (1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-phenyl-pentyl)-amide; [0440]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-3,5-dimethyl-cyclohexyl)-butyl]-amide; [0441]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-3,5-dimethyl-cyclohexyl)-butyl]-amide; [0442]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-cycloheptyl)-butyl]-amide; [0443]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-cycloheptyl)-butyl]-amide; [0444]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-5-(3-fluoro-phenyl)-2(S)-hydroxy-pentyl]-amide; [0445]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-m-tolyl-pentyl)-amide; [0446]
  • quinoxaline-2-carboxylic acid (1(S)-benzyl-2(S)-hydroxy-4-isobutylcarbamoyl-butyl)-amide; [0447]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(2-hydroxy-adamantan-2-yl)-butyl]-amide; [0448]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(9-hydroxy-bicyclo[3.3.1 ]non-9-yl)-butyl]-amide; [0449]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-(2-hydroxy-adamantan-2-yl)-4-hydroxycarbamoyl-butyl]-amide; [0450]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-(9-hydroxy-bicyclo[3.3.1 ]non-9-yl)-4-hydroxycarbamoyl-butyl]-amide; [0451]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-(3-methoxy-phenyl)-pentyl]-amide; [0452]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-4-propyl-cyclohexyl)-butyl]-amide; [0453]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-4-propyl-cyclohexyl)-butyl]-amide; [0454]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-(4-methoxy-phenyl)-pentyl]-amide; [0455]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-4(S)-(4-ethyl-1-hydroxy-cyclohexyl)-2-hydroxy-butyl]-amide; [0456]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-4,4-dimethyl-cyclohexyl)-butyl]-amide; [0457]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-4,4-dimethyl-cyclohexyl )-but yl]-amide; [0458]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-butyl]-amide; [0459]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-(4,4-difluoro-1-hydroxy-cyclohexyl)-2(S)-hydroxy-4-hydroxycarbamoyl-but yl]-amide; and [0460]
  • quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-4-trifluoromethyl-cyclohexyl)-butyl]-amide. [0461]
  • The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis). in a mammal, preferably a human, comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier. [0462]
  • The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by inhibiting MIP-1α binding to the receptor CCR1 in a mammal, preferably a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier. Examples of such disorders and conditions are those enumerated in the preceding paragraph. [0463]
  • The present invention also relates to a method for treating or preventing a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis) in a mammal, preferably a human, comprising administering to a mammal in need of such treatment or prevention an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder or condition. [0464]
  • The present invention also relates to a method for treating or preventing a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal, preferably a human, comprising administering to a mammal in need of such treatment or prevention an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder or condition. [0465]
  • The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis) in a mammal, preferably a human, comprising a CCR1 receptor antagonizing effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [0466]
  • The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal, preferably a human, comprising a CCR1 receptor antagonizing effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [0467]
  • The present invention also relates to a method for treating or preventing a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis) in a mammal, preferably a human, comprising administering to a mammal in need of such treatment or prevention a CCR1 receptor antagonizing effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. [0468]
  • This invention also encompasses pharmaceutical compositions containing and methods of treating or preventing comprising administering prodrugs of compounds of the formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain. Prodrugs also include compounds of formula I in which the secondary amide and its β-hydroxy when taken together form a group of the formula [0469]
    Figure US20020198207A1-20021226-C00004
  • wherein R[0470] 1, R2, R3, R4 and R5 are as defined in formula I and U and V are independently carbonyl, methylene, SO2 or SO3, and b is an integer from one to three wherein each methylene group is optionally substituted with hydroxy.
    • DETAILED DESCRIPTION OF THE INVENTION
  • Compounds of the formula I may be prepared according to the following reaction schemes and discussion. Unless otherwise indicated g, n, m, p, and R[0471] 1 through R6 and structural formula I in the reaction Schemes and discussion that follow are as defined above.
    Figure US20020198207A1-20021226-C00005
  • Scheme 1 refers to the preparation of compounds of the formula I having the exact stereochemistry [0472]
    Figure US20020198207A1-20021226-C00006
  • Compounds of the formula Ia and Ib, or any of the intermediates thereof, can be separated by column chromatography according to methods well known to those of ordinary skill in the art, to yield pure compounds of the formula Ia and Ib. [0473]
  • Referring to Scheme 1, compounds of the formula I, wherein either or both R[0474] 4 or R5 are other than hydrogen, are prepared from compounds of the formula II (i.e. IIa and IIb) by reaction with a compound of the formula R4R5NH in a polar solvent at a temperature from about 0° C. to about 100° C., preferably the boiling point of the solvent used, i.e. 65° C. when methanol is the solvent. Suitable solvents include, alcohols, such as methanol, ethanol, or butanols or ethers such as glyme or dioxane (an acid catalyst is preferably used with an ether solvent). Preferably the solvent is dioxane.
  • Alternatively, compounds of formula I, wherein either or both R[0475] 4 and R5 are hydrogen, can be prepared from compounds of formula II, (i.e. IIa and IIb) by reaction with ammonia or another volatile amine in a polar solvent at a temperature from about −10° C. to about 35° C., preferably at about 30° C. Suitable solvents include, alcohols, such as methanol, ethanol, or butanols; or ethers such as glyme or dioxane (an acid catalyst may be used with an ether solvent). Preferably the solvent is methanol.
  • Compounds of formula II are prepared by coupling a compound of formula III (i.e. IIIa and IIIb) with an acid of the formula R[0476] 1CO2H. Such a coupling reaction is generally conducted at a temperature of about −30° C. to about 80° C., preferably about 0° C. to about 25° C. Examples of suitable coupling reagents which activate the carboxylic acid functionality are dicyclohexylcarbodiimide/hydroxybenzotriazole (DCC/HBT), N-3-dimethylaminopropyl-N′-ethylcarbodiimide (EDC)/HBT, 2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyl diimidazole (CDI)/dimethylaminopyridine (DMAP), and diethylphosphorylcyamide. The coupling is conducted in an inert solvent, preferably an aprotic solvent, such as acetonitirile, dichloromethane, chloroform, and dimethylformamide. The preferred solvent is dichloromethane.
  • For a discussion of other conditions used for amide coupling see Houben-Weyl, Vol. XV, part II, E. Wunsch, Ed., George Theime Veriag, 1974, Stuttgart, and those described in M. Bodanszky. [0477] Principles of Peptide Synthesis, Springer-Verlag, Berlin (1984) and The Peptides, Analysis, Synthesis and Biology (ed. E. Gross and J. Meienhofer), Vois 1-5. (Academic Press, New York) 1979-1983.
  • The compounds of formula III, wherein R[0478] 3 is (C1-C10)alkyl, (C3-C10)cycloalkyl-(CH2)n—, (C2-C9)heterocycloalkyl-(CH2)n—, (C2-C9)heteroaryl-(CH2)n—, or aryl-(CH2)n— can be prepared by deprotection of compounds of the formula IV (i.e. IVa and lVb). Suitable protecting groups, of the formula P, include carbobenzyloxy, t-butoxy carbonyl or 9-fluorenyl-methylenoxy carbonyl.
  • For example: [0479]
  • (a) If the protecting group, P, of the compound of the formula IV is carbobenzyloxy, the latter may be removed by hydrogenation with a nobel metal catalyst such as palladium or palladium hydroxide on carbon in the presence of hydrogen. The hydrogenation is generally conducted at a temperature of about 0° C. to about 100° C., preferably about 20° C. to 50° C. [0480]
  • (b) If the protecting group, P, is t-butoxycarbonyl group, such group may be removed by acidolysis. Acidolysis may be conducted with HCl in dioxane or with trifluoracetic acid in methylene chloride at a temperature of about −30° C. to about −70° C., preferably about −5° C. to about 35° C. [0481]
  • (c) If the protecting group, P, is 9-fluorenylmethylenoxycarbonyl, such group may be removed by treatment with an amine base, preferably piperidine. This reaction may be run in piperidine as solvent at 10° C. to about 100° C., preferably at 25° C. [0482]
  • Compounds of the formula III, wherein R[0483] 3 is substituted (C1-C10)alkyl, (C3-C10)cycloalkyl-(CH2)n— or (C2-C9)heterocycloalkyl-(CH2)n— may be prepared from compounds of the formula IV, wherein R3 is (C1-C10)alkyl, (C3-C10)cycloalkyl-(CH2)n— or (C2-C9)heterocycloalkyl-(CH2)n—, wherein one of the carbon-carbon single bonds is replaced by a carbon-carbon double bond, by methods well known to those of ordinary skill in the art. Specifically, one example of introduction of substitution into the R3 group, a compound of formula III, wherein R3 is (C1-C10)alkyl substituted by one to three fluoro groups can be prepared from compounds of the formula IV, wherein R3 is (C1-C10)alkyl, wherein one of the carbon-carbon single bonds of said (C1-C10)alkyl has been replaced by a carbon-carbon double bond, by reaction with hydrogen fluoride in pyridine (i.e. pyridinium poly(hydrogen fluoride), in a reaction inert solvent. Suitable solvents include cyclohexane, toluene or benzene, preferably benzene. The aforesaid reaction is run at a temperature from about −78° C. to about 35° C. Preferably, this reaction is carried out in benzene at about 25° C.
  • Compounds of the formula IV, wherein R[0484] 3 is (C1-C10)alkyl, (C3-C10)cycloalkyl-(CH2)n—(C2-C9)heterocycloalkyl-(CH2)n—, (C2-C9)heteroaryl-(CH2)n— or aryl-(CH2)n—, wherein n is other than zero, can be prepared by reaction of a compound of formula V with a compound of the formula R3—L, wherein L is a leaving group, in the presence of a strong base in an aprotic polar solvent. Suitable leaving groups include chloro, fluoro, bromo, iodo, mesylate, triflate or tosylate. Preferably, the leaving group is a triflate, iodide or bromide. Triflates may be easily prepared according to the method of Beard, et al., J Org Chem., 38, 3673 (1973). Suitable bases include lithium dialkyl amides such as lithium N-isopropyl-N-cyclohexylamide or potassium hydride. Suitable solvents include ethers (such as THF, glyme or dioxane) benzene or toluene, preferably THF. The aforesaid reaction is conducted at about −78° C. to about 0° C., preferably at about −78° C.
  • Alternatively, compounds of the formula IV, wherein R[0485] 3 is (C1-C10)alkyl, (C3-C10)cycloalkyl-(CH2)n— or (C2-C9)heterocycloalkyl-(CH2)n— can be prepared by reaction of a compound of formula V with an aldehyde or ketone precursor of R3 in an aldol condensation. For example, a compound of the formula V can be reacted with a compound of the formula R3(═O) in the presence of a base, to form an aldol intermediate of the formula
    Figure US20020198207A1-20021226-C00007
  • which may be isolated and taken on to final product or converted directly in the same reaction step to a compound of the formula IV by the loss of water. The degree of completion for the conversion of compounds of the formula II to the aldol product of formula I may be assessed using one or more analytical techniques, such as thin layer chromatography (tlc) or mass spectrometry. In some instances it may be possible or desirable to isolate the intermediate of formula VI. In such case, the compound of formula VI may be converted into the compound of formula IV by the elimination of water using techniques which are familiar to those skilled in the art, for example, by heating to the reflux temperature a solution of the compound of formula VI in a solvent such as benzene, toluene or xylene, in the presence of a catalytic amount of phosphorous pentoxide, benzene- or p-toluene-sulfonic acid with provision for the removal of the water generated, preferably (methoxycarbonylsulfamoyl)-triethylammonium hydroxide (Burgess reagent). Such water removal techniques may involve the use of molecular sieves or a Dean-Stark trap to isolate the water created as an azeotrope with the solvent. [0486]
  • The aldol reaction is typically carried out in a polar solvent such as DMSO, DMF, tetrahydrofuran (THF), methanol or ethanol, at a temperature from about −78° C. to about 80° C. Preferably, this reaction is carried out in THF at about −78° C. Suitable bases for use in the aldol formation step include potassium carbonate (K[0487] 2CO3), sodium carbonate (Na2CO3), sodium hydride (NaH), sodium methoxide, potassium-tert.-butoxide, lithium diisopropylamide, pyrrolidine and piperidine. Lithium diisopropylamide is preferred. Aldol condensations are described in “Modern Synthetic Reactions,” Herbert O. House, 2d. Edition, W. A. Benjamin, Menlo Park, Calif., 629-682 (1972), J. Org. Chem., 49, 2455 (1984), and Tetrahedron, 38 (20), 3059 (1982).
  • Compounds of the formula IV wherein R[0488] 3 is unsaturated can be converted to saturated analogues by hydrogenating the compounds containing a carbon-carbon double bond, using standard techniques that are well known to those skilled in the art. For example, reduction of the double bond may be effected with hydrogen gas (H2), using catalysts such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO4), platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), in an appropriate solvent such as methanol, ethanol, THF, dioxane or ethyl acetate, at a pressure from about 1 to about 5 atmospheres and a temperature from about 10° C. to about 60° C., as described in Catalytic Hydrogenation in Organic Synthesis, Paul Rylander, Academic Press Inc., San Diego, 31-63 (1979). The following conditions are preferred: Pd on carbon, methanol at 25° C. and 50 psi of hydrogen gas pressure. This method also provides for introduction of hydrogen isotopes (Le deuterium, tritium) by replacing 1H2 with 2H2 or 3H2 in the above procedure.
  • An alternative procedure employing the use of reagents such as ammonium formate and Pd/C in methanol at the reflux temperature under an inert atmosphere (e.g., nitrogen or argon gas) is also effective in reducing the carbon-carbon double bond of compounds of the formula I. Another alternative method involves selective reduction of the carbon-carbon bond. This can be accomplished using samarium and iodine or samarium iodide (Sml[0489] 2) in methanol or ethanol at about room temperature, as described by R. Yanada et. al., Synlett., 443-4 (1995).
  • Compounds of the formula V can be prepared by methods well known to those of ordinary skill in the art or are commercially available. Specifically, compounds of the formula Va and Vb (shown below) can be prepared by the method of Fray et al., ([0490] J. Org. Chem., 51, 4828-4833 (1986)) using an (S)-aldehyde of the formula
    Figure US20020198207A1-20021226-C00008
  • Compounds of the formula VII are prepared by reducing amino acids or amino esters to alcohols (Stanfield et al., [0491] J. Org. Chem. 46, 4799-4800 (1981), Soai et al., Bull. Chem. Soc. Jpn., 57, 2327 (1984)) followed by oxidation of the alcohols to aldehydes of the formula VII (Luly et al., J.Orq. Chem., 53 (26), 6109-6112 (1988) and Denis et al., J Orq. Chem., 56 (24), 6939-6942 (1991).). Un-natural amino acids can be prepared according to the method of Myers et al., Tet. Lett. 36, (1995) and Myers et al. J. Am. Chem. Soc., 117, 8488-8489 (1995).
  • Alternatively, compounds of the formula V can also be made by the method of DeCamp et al., ([0492] Tetrahedron Lett., 32, 1867 (1991)).
  • Compounds of the formula I, with the exact stereochemistry [0493]
    Figure US20020198207A1-20021226-C00009
  • can be prepared according to the methods of Scheme 1, using either the minor lactone diastereomer of the formula, [0494]
    Figure US20020198207A1-20021226-C00010
  • which can be prepared by the method of Fray, supra, from the (S)-aldehyde, or the alternate diastereomeric pair of the formula [0495]
    Figure US20020198207A1-20021226-C00011
  • which can be prepared using the corresponding (R)-aldehyde according to the method of Fray, supra. [0496]
  • Aldehyde or ketone precursors of the group R[0497] 3 are commercially available (e.g., -cyclohexanone) or can be made by methods well known to those of ordinary skill in the art, such as described in J. Am. Chem. Soc., 90, 7001 (1968) and J. Ore. Chem., 40, 574 (1975).
  • Unless indicated otherwise, the pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere). [0498]
  • The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained. [0499]
  • The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts. [0500]
  • Those compounds of the formula I which are also acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I. These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields. [0501]
  • Compounds of the formula I and their pharmaceutically acceptable salts (hereinafter also referred to, collectively, as “the active compounds”) are potent antagonists of the CCR1 receptors. The active compounds are useful in the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis). [0502]
  • The activity of the compounds of the invention can be assessed according to procedures know to those of ordinary skill in the art. Examples of recognized methods for determining CCR1 induced migration can be found in Coligan, J. E., Kruisbeek, A. M., Margulies, D. H., Shevach, E. M., Strober, W. editors: [0503] Current Protocols In Immunology, 6.12.1-6.12.3. (John Wiley and Sons, NY, 1991). One specific example of how to determine the activity of a compound for inhibiting migration is described in detail below.
    • Chemotaxis Assay
  • The ability of compounds to inhibit the chemotaxis to various chemokines can be evaluated using standard 48 or 96 well Boyden Chambers with a 5 micron polycarbonate filter. All reagents and cells can be prepared in standard RPMI (BioWhitikker Inc.) tissue culture medium supplemented with 1 mg/ml of bovine serum albumin. Briefly, MIP-1α (Peprotech, Inc., P.O. Box 275, Rocky Hill N.J.) or other test agonists, were placed into the lower chambers of the Boyden chamber. A polycarbonate filter was then applied and the upper chamber fastened. The amount of agonist chosen is that determined to give the maximal amount of chemotaxis in this system (e.g., 1 nM for MIP-1α should be adequate). [0504]
  • THP-1 cells (ATCC TIB-202), primary human monocytes, or primary lymphocytes, isolated by standard techniques can then be added to the upper chambers in triplicate together with various concentrations of the test compound. Compound dilutions can be prepared using standard serological techniques and are mixed with cells prior to adding to the chamber. [0505]
  • After a suitable incubation period at 37 degrees centigrade (e.g. 3.5 hours for THP-1 cells, 90 minutes for primary monocytes), the chamber is removed, the cells in the upper chamber aspirated, the upper part of the filter wiped and the number of cells migrating can be determined according to the following method. [0506]
  • For THP-1 cells, the chamber (a 96 well variety manufactured by Neuroprobe) can be centrifuged to push cells off the lower chamber and the number of cells can be quantitated against a standard curve by a color change of the dye fluorocein diacetate. [0507]
  • For primary human monocytes, or lymphocytes, the filter can be stained with Dif Quik® dye (American Scientific Products) and the number of cells migrating can be determined microscopically. [0508]
  • The number of cells migrating in the presence of the compound are divided by the number of cells migrating in control wells (without the compound). The quotant is the % inhibition for the compound which can then be plotted using standard graphics techniques against the concentration of compound used. The 50% inhibition point is then determined using a line fit analysis for all concentrations tested. The line fit for all data points must have an coefficient of correlation (R squared) of >90% to be considered a valid assay. [0509]
  • All of the compounds of the invention that were tested had IC 50 of less than 25 μM, in the Chemotaxis assay. [0510]
  • The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation. The active compounds of the invention may also be formulated for sustained delivery. [0511]
  • For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). [0512]
  • For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner. [0513]
  • The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [0514]
  • The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. [0515]
  • For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch. [0516]
  • A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., rheumatoid arthritis) is 0.1 to 1000 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day. [0517]
  • Aerosol formulations for treatment of the conditions referred to above (e.g., rheumatoid arthritis) in the average adult human are preferably arranged so that each metered dose or “puff” of aerosol contains 20 μg to 1000 μg of the compound of the invention. The overall daily dose with an aerosol will be within the range 0.1 mg to 1000 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time. [0518]
  • The active agents can be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in U.S. Pat. Nos. 3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397. [0519]
  • The compounds of the invention can also be utilized in combination therapy with other therapeutic agents such as with T-cell immunosuppressant agents such as cyclosporin A and FK-506, with steroid sparing agents such as Cellcept), or with classical anti-inflammatory agents (e.g. cyclooxygenase/lipoxegenase inhibitors) such as tenidap, aspirin, acetaminophen, naproxen and piroxicam. [0520]
  • The following Examples illustrate the preparation of the compounds of the present invention. Melting points are uncorrected. NMR data are reported in parts per million (6) and are referenced to the deuterium lock signal from the sample solvent (deuteriochloroform unless otherwise specified). Commercial reagents were utilized without further purification. THF refers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. Chromatography refers to column chromatography performed using 32-63 mm silica gel and executed under nitrogen pressure (flash chromatography) conditions. Low Resolution Mass Spectra (LRMS) were recorded on either a Hewlett Packard 5989(, utilizing chemical ionization (ammonium), or a Fisons (or Micro Mass) Atmospheric Pressure Chemical Ionization (APCI) platform which uses a 50/50 mixture of acetonitrile/water with 0.1% formic acid as the ionizing agent. Room or ambient temperature refers to 20-25° C. All non-aqueous reactions were run under a nitrogen atmosphere for convenience and to maximize yields. Concentration at reduced pressure means that a rotary evaporator was used. The names for the compounds of the invention were created by the Autonom 2.0 PC-batch version from Beilstein Informationssysteme GmbH (ISBN 3-89536-976-4).[0521]
    • EXAMPLE 1
  • Quinoline-3-carboxylic Acid (1(S)-Cyclohexylmethyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl-6-enyl)-amide [0522]
    • Method A
  • Quinoline-3-carboxylic Acid {1-[4-(2-methylpropen-2-yl)-5-oxo-tetrahydrofuran-2-yl]-2-cyclohexyl-ethyl}-amide [0523]
  • To a solution of 1-{4-(2-methylpropen-2-yl)-[5-oxo-tetrahydrofuran-2-yl]-2-cyclohexyl-ethyl}-carbamic acid tert-butyl ester (302 mg, 0.83 mmol)(prepared according to the method of Fray, supra, except that (S)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-1-propionaldehyde is the starting material aldehyde) in 15 mL of methylene chloride was added 1.5 mL of trifluoroacetic acid. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours at which time the solvent was removed by azeotropic distillation under reduced pressure, using toluene as a cosolvent during the distillation. The resulting crude oil was dissolved in methylene chloride (5 mL) and quinoline-3-carboxylic acid (219 mg, 1.26 mmol), hydroxybenzotriazole (HOBT)(188 mg, 1.39 mmol), triethylamine (0.25 mL, 1.80 mmol) and N-3-dimethylaminopropyl-N′-ethylcarbodiimide (EDC)(248 mg, 1.29 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The solution was transferred to a separatory funnel with 15 mL of methylene chloride and washed with 10% citric acid, saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and the solvent removed in vacuo. The remaining crude oil was purified by silica gel chromatography eluting with 3:1 hexanes:ethyl acetate to provide quinoline-3-carboxylic acid {1(S)-[4(R)-(2-methylpropen-2-yl)-5-oxo-tetrahydrofuran-2(S)-yl]-2-cyclohexyl-ethyl}-amide as a white foam (236 mg, 67%). [0524]
  • LRMS: 421 (MH+); [0525] 1H NMR(300 MHz, CDCl3): δ 0.90-1.89 (m, 13H), 1.63 (s, 3H), 2.03-2.14 (m, 2H), 2.38 (m, 2H), 2.48 (d, 1H, J=14.6 Hz), 2.73 (m, 1H), 4.63 (m, 2H), 4.69 (s, 1H), 4.79 (s, 1H), 6.9 (brs, 1H), 7.59 (t, 1H, J=7.8 Hz), 7.77 (t, 1H, J=8.4 Hz), 7.88 (d, 1H, J=8.3 Hz), 8.08 (d, 1H, J=8.4 Hz), 8.67 (s, 1H), 9.37 (d, 1H, J=2.1 Hz).
    • Method B
  • Quinoline-3-carboxylic Acid (1(S)-Cyclohexylmethyl-2(S)-hydroxy-6-methyl-4(R)-methylcarbamoyl-heptyl-6-enyl)-amide [0526]
  • Methylamine was bubbled into a solution of the product from Method A (55 mg, 0.129 mmol) in methanol (2.5 mL). The solution was stirred for 2 hours at room temperature and the solvent was removed under reduced pressure to provide the title compound (57 mg, 98%) as a pure white solid. [0527]
  • LRMS: 453 (MH+), 421, 283, 173; [0528] 1H NMR (300 MHz, CDCl3): δ 0.82-1.87 (m, 13H), 1.65 (s, 3H), 2.13 (dd, 1H, J=14.1, 8.7 Hz), 2.38 (d, 1H, J=14.2 Hz), 2.71 (d, 3H, J=4.7 Hz), 2.74 (m, 1H), 3.77 (d, 1H, J=8.7), 4.23 (br, 1H), 4.69 (s, 1H), 4.72 (s, 1H), 5.03 (brs, 1H), 6.60 (q, 1H, J=4.7 Hz), 7.24 (d, 1H, J=9.3), 7.54 (t, 1H, J=7.1), 7.73 (t, 1H, J=7.1 Hz), 7.81 (d, 1H, J=7.1 Hz), 8.04 (d, 1H, J=8.4), 8.61 (d, 1H, J=1.9), 9.33 (s, 1H).
    • EXAMPLE 2
  • Quinoxaline-2-carboxylic Acid (1(S)-Benzyl-4(R)-benzylcarbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide [0529]
    • Allylic Alkylation Method C
  • {1(S)-[4(R)-(3-Methyl-but-2-enyl)-5-oxo-tetrahydro-furan-2(S)-yl]-1-2-phenyl-ethyl}-carbamic Acid Tert-Butyl Ester [0530]
  • To a flame dried round bottom flask under a nitrogen atmosphere was added tetrahydrofuran (40 mL) followed by 1,1,1,3,3,3-hexamethyldisilazane (8 mL, 37.8 mmol). The mixture was cooled to 0° C. and n-butyl lithium (14.5 mL of a 2.5 M solution in hexanes, 36.0 mmol) was added. The mixture was stirred for 15 minutes, then cooled to −78° C. in dry ice/acetone bath. {1(S)-[5-Oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (5 g, 16.4 mmol) (prepared by the method of Fray, J. Org. Chem., (51) 4828 (1986)) dissolved in tetrahydrofuran (50 mL) was added dropwise via syringe and stirring continued for 30 minutes. A solution of 4-bromo-2-methyl-2-butene (2.07 mL, 18.0 mmol) in 40 mL of THF was added dropwise via syringe. Stirring was continued for 3 hours during which time the temperature rose to −60° C. The mixture was quenched by slow addition of saturated, aqueous ammonium chloride (25 mL). Upon warming to room temperature, the solution was diluted with ether (300 mL) and transferred to a separatory funnel. The organic phase was washed with saturated aqueous citric acid (2×100 mL), saturated aqueous sodium bicarbonate (NaHCO[0531] 3)(2×100 mL), and 100 mL brine. The organic layer was dried over magnesium sulfate (MgSO4) and the solvent removed under reduced pressure. Thin layer chromatography in 1:2 hexane/diethyl ether (Et2O) revealed product with an Rf of 0.8. The resulting crude oil was chromatographed on silica gel (225 g) eluting with 2:1 hexanes/diethyl ether to provide 4.73 g (77%) of the title compound. TLC: 1:2 Hexanes/Et2O Rf: 0.8. 1H NMR (400 MHz, CDCl3): δ 7.27 ppm (5H, m), 5.02 (1H, b), 4.52 (1H, d, J=9.3 Hz), 4.42 (1H, t, J=7.1 Hz), 3.98 (1H, dt, J=8.5, 7.8 Hz), 2.93 (2H, m), 2.88 (1H, b), 2.68 (1H, m), 2.41 (1H, m), 2.24 (1H, m), 1.92 (1H, m), 1.65 (3H, s), 1.58 (3H, s), 1.37 (9H, s).
    • Method D
  • 5(S)-(1(S)-Amino-2-phenyl-ethyl)-3(R)-(3-fluoro-3-methyl-butyl)-dihydro-furan-2-one [0532]
  • To a solution of product from Method C (9.81 g, 26.3 mmol) in dry benzene (300 mL) was added HF-pyridine (88 mL). The resulting solution was stirred at ambient temperature for 4 hours, then transferred to a 4 L beaker. To this was added ice, and the pH was slowly adjusted to 8-9 by addition of 2 M aqueous sodium hydroxide (NaOH[0533] aq). The mixture was extracted with ethyl acetate (EtOAc) and the organics dried over magnesium sulfate, and then filtered and concentrated. Chromatography on silica gel yielded the title compound (5.68 g, 74%).
    • Method E
  • Quinoxaline-2-carboxylic Acid {1(S)-[4(R)-(3-fluoro-3-methyl-butyl)-5-oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-amide [0534]
  • To a solution of quinoxaline carboxylic acid (5.05 g, 29.0 mmol) in methylene chloride (100 mL) was added dimethylaminopyridine (DMAP) (3.55 g, 29.0 mmol) and EDCI (5.55 g, 29.0 mmol). The solution was stirred 10 minutes, then the product from Method D, above, (5.68 g, 19.4 mmol) was added in one portion. The solution was stirred for 12 hours, then diluted with diethyl ether and washed with saturated aqueous brine. The organics were dried over magnesium sulfate, and then filtered and concentrated. The crude product was purified by silica gel chromatography to yield the title compound (5.62 g, 64%). [0535]
    • Method F
  • Quinoxaline-2-carboxylic Acid (1(S)-Benzyl-4(R)-benzylcarbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide [0536]
  • To a solution of the product from Method E (0.10 g, 0.22 mmol) in dioxane (2 mL) was added glacial acetic acid (0.038 mL, 0.66 mmol) and benzylamine (approx. 1 mL, excess). The resulting solution was warmed to reflux for 1 hour, cooled to ambient temperature and diluted with water. The solution was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate (MgSO[0537] 4), filtered and concentrated. Chromatography on silica gel, followed by recrystallization from methylene chloride/hexanes gave the title compound (0.068 g, 56%). m.p. 183-184° C.
    • EXAMPLE 3 Method F′
  • Quinoxaline-2-carboxylic Acid (1-benzyl-7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl)-amide [0538]
  • Hydroxylamine hydrochloride (1.55 g, 22.4 mmol) and KOH (1.51 g, 26.7 mmol) were combined in anhydrous methanol (20 mL) and stirred for 30 minutes under a dry nitrogen atmosphere, and then filtered. To the resulting filtrate was added the product from Method E (500 mg, 1.17 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the residue solvated in EtOAc (50 mL) and transferred to a separated funnel. The organic layer was washed with water and brine and dried (MgSO4). After filtration the solvent was removed in vacuo and the remaining residue recrystallized (methylene chloride/Hexanes) to give a pale yellow solid (330 mg, 58%) m.p. 165-166° C. [0539]
    • EXAMPLE 4
  • Quinoxaline-2-carboxylic Acid (1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-7-methyl-octyl)-amide [0540]
    • METHOD G Alkene Hydrogenation
  • {1(S)-[4(R)-(3-Methyl-butyl)-5-oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic Acid Tert-Butyl Ester [0541]
  • The product from Method C, from Example 2 above, (3.0 g, 8.04 mmol) was placed in a 250 mL Parr Shaker bottle and dissolved in ethanol (50 mL). Under a nitrogen atmosphere, Palladium (Pd) on activated carbon (0.30 g, 10% Pd content) was added to the solution. The mixture was placed on a Parr Shaker hydrogenator at 50 psi for 5 hours at room temperature. The hydrogenation mixture was diluted with ethyl acetate and then poured through a Celite® pad while washing copiously with ethyl acetate. The solvent of the filtrate was removed in vacuo to yield the title compound, 2.63 g (88%). [0542]
  • [0543] 1H NMR (400 MHz, CDCl3): δ 7.27 (5H, m), 4.54 (1H, d, J=9.8 Hz), 4.46 (1H, t, J=6.9), 4.0 (1H, dt), 2.89 (2H, d, J=8.1), 2.57 (1H, m), 2.32 (1H, b), 1.89 (1H, m), 1.79 (1H, m), 1.52 (2H, m), 1.37 (9H, s), 1.23 (2H, m), 0.86 (6H, d, J=6.6 Hz).
  • The product from Method G was converted into the title compound by procedures analogous to those of Methods A and B except that quinoline-3-carboxylic acid is replaced with quinoxaline-2-carboxylic acid and methylamine is replaced with ammonia gas to yield 0.095 g (72%) of the title compound. [0544]
  • [0545] 1H NMR (400 MHz, CDCl3): δ 9.61(1H, s), 8.32 (1H, d, J=8.9 Hz), 8.16 (2H, m), 7.86 (2H, m), 7.28 (10H, m), 7.19 (1H, m), 5.70 (1H, b), 5.29 (1H, b), 4.27 (1H, m), 8.21 (1H, d, J=4.4 Hz), 3.91 (1H, m), 3.11 (2H, m), 2.46 (1H, m), 1.74 (1H, t, J=6.4 Hz), 1.61 (1H, m), 1.42 (2H, m), 1.17 (1H, m), 1.09 (1H, m), 0.81 (3H, d, J=7.1 Hz), 0.79 (3H, d, J=7.1 Hz). 13C NMR (100 MHz, CDCl3):d 179.11, 163.73, 143.90, 143.76, 143.15, 140.28, 137.96, 131.68, 130.84, 129.84, 129.44, 129.25, 128.58, 126.60, 68.55, 55.90, 43.44, 38.39, 36.90, 36.70, 29.77, 28.03, 22.42
    • EXAMPLE 5
  • Quinoxaline-2-carboxylic Acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-7.7-dimethyl-octyl)-amide [0546]
    • Method H Triflate Alkylation
  • {-[4-(3,3-Dimethyl-butyl)-5-oxo-tetrahydro-furan-2-yl]-2-phenyl-ethyl)-carbamic Acid Tert-Butyl Ester [0547]
  • To a flame dried round bottom flask under a nitrogen atmosphere was added terahydrofuran (THF) (2 mL) and 1,1,1,3,3,3 hexamethyldisilazane (0.82 mL, 3.88 mmol). The mixture was cooled to 0° C. and n-butyl lithium (1.48 mL of a 2.5 M solution in hexanes, 3.72 mmol) was added dropwise via syringe. The mixture was stirred for 15 minutes and then cooled to −78° C. {1(S)-[5-Oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (0.52 9, 1.69 mmol prepared by the method of Fray, supra) dissolved in tetrahydrofuran (2 mL) was slowly added to the solution via syringe and the solution was stirred for 1 hour. A solution of the desired triflate, i.e. 3,3-dimethylbutyl triflate (0.92 g, 3.37 mmol)(prepared according to the method of Beard, et al., [0548] J Orq Chem., 38, 3673 (1973)) in tetrahydrofuran (2 mL) was added dropwise via syringe and the mixture was stirred for 2 hours at −78° C. The mixture was quenched by addition of saturated aqueous ammonium chloride (NH4Cl) (25 mL). Upon warming to room temperature, the mixture was diluted with ethyl acetate (40 mL), transferred to a separatory funnel, and washed with saturated aqueous NH4Cl (2×40 mL), saturated NaHCO3 (2×40 mL), and brine (40 mL). The organic layers were dried (MgSO4) and the solvent removed under reduced pressure. The resulting crude oil was chromatographed on silica gel (25 g) eluting with 100 mL 5:1 hexanes/ethyl acetate followed by 400 mL 4:1 hexanes/ethyl acetate. This provided 0.36 g (50%) of the title compound.
  • TLC: (4:1 hexanes/ethyl acetate) R[0549] f: 0.3. 1H NMR (400 MHz, CDCl3): δ 7.25 (m, 7H), 6.92 (t, 1H, J=7.5 Hz), 6.85 (d, 2H, J=8.1 Hz), 4.67 (d, 2H, J=6.0 Hz), 4.49 (t, 1H, J=9.6 Hz), 4.06 (m, 3H), 2.89 (m, 3H), 2.43 (m, 1H), 2.26 (m, 1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.37 (s, 9H).
  • The product of Method H was converted to the title compound by procedures analogous to those of Methods A and B, from Example 1, except that quinoline-3-carboxylic acid is replaced with quinoxaline-2-carboxylic acid and methylamine is replaced with ammonia gas. [0550]
    • EXAMPLE 6
  • Quinoxaline-2-carboxylic Acid [1(S)-benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-cyclohexyl)-butyl]-amide and [0551]
  • Quinoxaline-2-carboxylic Acid [1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-4-(1-hydroxy-cyclohexyl)-butyl]-amide [0552]
    • Method I
  • {1(S)-[4(S)-(1-Hydroxy-cyclohexyl)-5-oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic Acid Tert-Butyl Ester [0553]
  • To a solution of diisopropylamine (0.90 mL, 6.88 mmol) in THF (10 mL) at 0° C. was added a solution of n-butyl lithium (2.7 mL, 6.71 mmol, 2.5 M in hexanes). The solution was stirred for 15 minutes, then cooled to −78° C. To this was added dropwise a solution of {1(S)-[5-Oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (1.0 g, 3.27 mmol prepared as in example 2, method C) in tetrahydrofuran (10 mL) and the reaction was stirred an additional 30 minutes. To this was added the appropriate ketone, e.g., cyclohexanone) (0.37 mL, 3.60 mmol), and the solution was warmed to ambient temperature. The reaction was quenched by addition of saturated aqueous bicarbonated NaHCO[0554] 3) solution and the mixture extracted with diethyl ether. The combined organics were dried over magnesium sulfate (MgSO4), filtered and concentrated. Chromatography on silica gel gave a mixture of separable diastereomers of {[1(S)-[4(S)-(1-hydroxy-cyclohexyl)-5-oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (0.687 g) and {f(S)-[4(R)-(1-hydroxy-cyclohexyl)-5-oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (0.269 g) in 67% overall yield.
  • The products from Method I were converted to the title compounds by procedures analogous to those of Methods A and B, from Example 1, except that quinoline-3-carboxylic acid is replaced with quinoxaline-2-carboxylic acid and methylamine is replaced with ammonia gas. [0555]
    • EXAMPLE 7
  • Fluoro-quinoline-3-carboxylic Acid (1(S)-benzyl-4(S)-carbamoyl-4-cyclohexyl-2(S)-hydroxy-butyl)-amide and [0556]
  • Fluoro-quinoline-3-carboxylic Acid (1(S)-benzyl-4(R)-carbamoyl-4-cyclohexyl-2(S)-hydroxy-butyl)-amide [0557]
    • Method J
  • {1(S)-[4(S)-(1-Hydroxy-cyclohexyl)-5-oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic Acid Tert-Butyl Ester [0558]
  • To a solution of the title compound from Method I, Example 5, (1.38 g, 3.42 mmol) in benzene (40 mL) was added (methoxycarbonylsulfamoyl)-triethylammonium hydroxide, inner salt (Burgess reagent) (1.30 g, 5.47 mmol) and the solution was warmed to reflux for 2 hours. The reaction was diluted with diethyl ether and washed with saturated aqueous brine. The organics were dried over magnesium sulfate, filtered and concentrated to give the crude elimination product. This was directly dissolved in 5:1 tetrahydrofuran/methanol (THF/MeOH)(30 mL) and transferred to a Parr flask containing 10% palladium on carbon (Pd/C) (1 g). The mixture was hydrogenated at 35 psi for 1.5 hours, then filtered through a pad of Celite and the filtrate concentrated. Chromatography on silica gel yielded the title compound as a mixture of separable diastereomers {1(S)-[4(S)-(1-hydroxy-cyclohexyl)-5-oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (0.53 g) and {1(S)-[4(R)-(1-hydroxy-cyclohexyl)-5-oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (0.29 g) in 62% overall yield. [0559]
  • The products from Method J were converted to the title compounds by procedures analogous to those of Methods A and B, from Example 1, except that quinoline-3-carboxylic acid is replaced with quinoxaline-2-carboxylic acid and methylamine is replaced with ammonia gas. [0560]
    • EXAMPLES 8-315
  • The compounds from Table 1 were prepared according to the methods described above, substituting where appropriate the correct R[0561] 2 aldehyde, R3 group (such as allylic halide, alkyl triflate, ketone, etc.), R1 carboxylic acid or R4 and R5 amine where appropriate.
    TABLE 1
    EXAM-
    PLE NAME M.P. (° C.) LRMS
    8. Quinoxaline-2-carboxylic acid 455
    1(S)-cyclohexylmethyl-2(S)-hydroxy-6-
    methyl-4(R)-methylcarbamoyl-heptyl)-
    amide
    9. Quinoxaline-2-carboxylic acid
    (6-chloro-1-cyclohexylmethyl-2(S)-
    hydroxy-4(S)-methylcarbamoyl-hept-6-
    enyl)-amide
    10. Quinoline-3-carboxylic acid 155-157 414
    (2(S)-hydroxy-1(S)-isobutyl-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    11. Quinoxaline-2-carboxylic acid 69-71 415
    1(S)-sec-butyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    12. Quinoline-3-carboxylic acid 452
    1(S)-cyclohexylmethyl-2(S)-hydroxy-6-
    methyl-4(R)-methylcarbamoyl-hept-6-
    enyl)-amide
    13. Quinoxaline-2-carboxylic acid 453
    1(S)-cyclohexylmethyl-2(S)-hydroxy-6-
    methyl-4(R)-methylcarbamoyl-hept-6-
    enyl)-amide
    14. N-1(S)-Cyclohexylmethyl-2(S)-hydroxy- 115-119
    6-methyl-4(R)-methylcarbamoyl-
    heptyl)-5-phenyl-nicotinamide
    15. Quinoline-3-carboxylic acid 1(S)- 162-163
    benzyl-2(S)-hydroxy-6-methyl-4(R)-
    methylcarbamoyl-heptyl)-amide
    16. Quinoxaline-2-carboxylic acid 467
    1(S)-cyclohexylmethyl-4(R)-
    dimethylcarbamoyl-2(S)-hydroxy-6-
    methyl-hept-6-enyl)-amide
    17. Quinoline-3-carboxylic acid 171-175 453,
    1(S)-cyclohexylmethyl-2(S)-hydroxy-6- 436
    methyl-4(S)-methylcarbamoyl-heptyl)-
    amide
    18. Quinoxaline-2-carboxylic acid 455,
    1(S)-cyclohexylmethyl-2(S)-hydroxy-6- 437
    methyl-4(S)-methylcarbamoyl-heptyl)-
    amide
    19. Isoquinoline-4-carboxylic acid 180-182 454
    1(S)-cyclohexylmethyl-2(S)-hydroxy-6-
    methyl-4(S)-methylcarbamoyl-heptyl)-
    amide
    20. Quinoline-3-carboxylic acid 186-188 440,
    (4(R)-carbamoyl-1(S)-cyclohexylmethyl- 478,
    2(S)-hydroxy-6-methyl-heptyl)-amide 423
    21. Quinoline-3-carboxylic acid (5- 170.5-172.5 494
    cyclohexyl-1(S)-cyclohexylmethyl-2(S)-
    hydroxy-4(R)-methylcarbamoyl-pentyl)-
    amide
    22. Quinoline-3-carboxylic acid 1(S)- 454
    cyclohexylmethyl-2(S)-hydroxy-6-
    methyl-4(R)-methylcarbamoyl-heptyl)-
    amide
    23. Quinoline-3-carboxylic acid   200-201.5 454
    1(S)-cyclohexylmethyl-2(S)-hydroxy-6-
    methyl-4(S)-methylcarbamoyl-heptyl)-
    amide
    24. Quinoline-3-carboxylic acid   199-200.5 488
    1(S)-cyclohexylmethyl-2(S)-hydroxy-
    4(R)-methylcarbamoyl-5-phenyl-
    pentyl)-amide
    25. Quinoxaline-2-carboxylic acid   109-110.5 489
    1(S)-cyclohexylmethyl-2(S)-hydroxy-
    4(R)-methylcarbamoyl-5-phenyl-
    pentyl)-amide
    26. Quinoline-3-carboxylic acid 142-144 490,
    1(S)-benzyl-4(R)-butylcarbamoyl-2(S)- 417
    hydroxy-6-methyl-heptyl)-amide
    27. Quinoline-3-carboxylic acid 148-150 488,
    1(S)-benzyl-4(R)-cyclobutylcarbamoyl- 417
    2(S)-hydroxy-6-methyl-heptyl)-amide
    28. Quinoline-3-carboxylic acid 158-162 524,
    1(S)-benzyl-4(R)-benzylcarbamoyl- 417
    2(S)-hydroxy-6-methyl-heptyl)-amide
    29. Quinoline-3-carboxylic acid 174-179 474
    1(S)-benzyl-4(R)-
    cyclopropylcarbamoyl-2(S)-hydroxy-6-
    methyl-heptyl)-amide
    30. Quinoline-3-carboxylic acid   190-192.5 448
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(S)-methylcarbamoyl-heptyl)-amide
    31. Quinoline-3-carboxylic acid 175-176 462
    1(S)-benzyl-4(R)-ethylcarbamoyl-2(S)-
    hydroxy-6-methyl-heptyl)-amide
    32. Quinoline-3-carboxylic acid 476
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-propylcarbamoyl-heptyl)-amide
    33. Quinoline-3-carboxylic acid 158-162 478
    [1-benzyl-2(S)-hydroxy-4(R)-(2-
    hydroxy-ethylcarbamoyl)-6-methyl-
    heptyl]-amide
    34. Cinnoline-4(R)-carboxylic acid   185-186.5 449
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    35. Isoquinoline-4-carboxylic acid 200-201 448
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    36. Quinoxaline-2-carboxylic acid 166-167 449
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    37. N-1(S)-Benzyl-2(S)-hydroxy-6-methyl- 184.5-185.5 478
    4(R)-methylcarbamoyl-heptyl)-5-
    bromo-nicotinamide
    38. Quinoline-3-carboxylic acid 454
    1(R)-cyclohexylmethyl-2(R)-hydroxy-6-
    methyl-4(S)-methylcarbamoyl-heptyl)-
    amide
    39. Quinoxaline-2-carboxylic acid 196-197 554
    [1(S)-(4-benzyloxy-benzyl)-2(S)-
    hydroxy-6-methyl-4(R)-
    methylcarbamoyl-heptyl]-amide,
    40. Quinoline-3-carboxylic acid 178-179 555
    [1(S)-(4-benzyloxy-benzyl)-2(S)-
    hydroxy-6-methyl-4(R)-
    methylcarbamoyl-heptyl]-amide
    41. Isoquinoline-1-carboxylic acid 178-179 448
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    42. Quinoline-4-carboxylic acid 189-192 448
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    43. Quinoline-6-carboxylic acid 165-167 448
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    44. Quinoline-3-carboxylic acid 220.5-222.5 464
    [2(S)-hydroxy-1(S)-(4-hydroxy-benzyl)-
    6-methyl-4(R)-methylcarbamoyl-
    heptyl]-amide
    45. Quinoline-2-carboxylic acid   160-161.5 449
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    46. Naphthalene-2-carboxylic acid 218-220 447
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    47. Quinoline-3-carboxylic acid 172-174 486
    1(S)-benzyl-5-cyclohex-1-enyl-2(S)-
    hydroxy-4(R)-methylcarbamoyl-pentyl)-
    amide
    48. Quinoline-3-carboxylic acid 153-154 504
    [1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-(3-methyl-butylcarbamoyl)-heptyl]-
    amide
    49. Quinoxaline-2-carboxylic acid 157-163 449
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(S)-methylcarbamoyl-heptyl)-amide
    50. Trifluoro-methanesulfonic acid 168-170 596
    4-{3(S)-hydroxy-7-methyl-5(R)-
    methylcarbamoyl-2(S)-[(quinoline-3-
    carbonyl)-amino]-octyl}-
    phenyl ester
    51. Trifluoro-methanesulfonic acid 597
    4-{3(S)-hydroxy-7-methyl-5(R)-
    methylcarbamoyl-2(S)-[(quinoxaline-
    2-carbonyl)-amino]-octyl}-phenyl ester
    52. Quinoline-3-carboxylic acid 185-187 488
    1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-
    4(R)-methylcarbamoyl-pentyl)-amide
    53. Quinoxaline-2-carboxylic acid 132-134 489,
    1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy- 471
    4(R)-methylcarbamoyl-pentyl)-amide
    54. Isoquinoline-3-carboxylic acid 150.5-151.5 488
    1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-
    4(R)-methylcarbamoyl-pentyl)-amide
    55. N-1(S)-Benzyl-5-cyclohexyl-2(S)-   199-200.5 518
    hydroxy-4(R)-methylcarbamoyl-pentyl)-
    5-bromo-nicotinamide
    56. Quinoline-3-carboxylic acid 1(S)- 472
    benzyl-2(S)-hydroxy-6-methyl-4(R)-
    prop-2-ynylcarbamoyl-heptyl)-amide
    57. Quinoline-3-carboxylic acid 456,
    1(S)-cyclohexylmethyl-2(S)-hydroxy- 438,
    4(R)-hydroxycarbamoyl-6-methyl- 423
    heptyl)-amide
    58. Quinoline-3-carboxylic acid 2(S)- 176-177 478
    hydroxy-1(S)-(4-methoxy-benzyl)-6-
    methyl-4(R)-methylcarbamoyl-heptyl]-
    amide
    59. Isoquinoline-3-carboxylic acid (5- 205-207 494
    cyclohexyl-1(S)-cyclohexylmethyl-2(S)-
    hydroxy-4(R)-methylcarbamoyl-pentyl)-
    amide,
    60. 5-Bromo-N-(5-cyclohexyl-1(S)- 173.5-175   444
    cyclohexylmethyl-2(S)-hydroxy-4(R)-
    methylcarbamoyl-pentyl)-nicotinamide
    61. Quinoxaline-2-carboxylic acid 479
    [2(S)-hydroxy-1(S)-(4-methoxy-benzyl)-
    6-methyl-4(R)-methylcarbamoyl-
    heptyl]-amide
    62. Isoquinoline-4-carboxylic acid 220.5-224   494
    (5-cyclohexyl-1(S)-cyclohexylmethyl-
    2(S)-hydroxy-4(R)-methylcarbamoyl-
    pentyl)-amide
    63. Quinoline-2-carboxylic acid 120-122 488
    1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-
    4(R)-methylcarbamoyl-pentyl)-amide
    64. lsoquinoline-4-carboxylic acid 177-180 488
    1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-
    4(R)-methylcarbamoyl-pentyl)-amide,
    65. Quinoxaline-2-carboxylic acid 170-172 465
    [2(S)-hydroxy-1(S)-(4-hydroxy-benzyl)-
    6-methyl-4(R)-methylcarbamoyl-
    heptyl]-amide,
    66. Quinoxaline-2-carboxylic acid 496
    (5-cyclohexyl-1(S)-cyclohexylmethyl-
    2(S)-hydroxy-4(R)-methylcarbamoyl-
    pentyl)-amide
    67. Quinoline-3-carboxylic acid 212.5-213.5 482
    [1(S)-(4-chloro-benzyl)-2(S)-hydroxy-6-
    methyl-4(R)-methylcarbamoyl-heptyl]-
    amide
    68. Quinoxaline-2-carboxylic acid 483
    [1(S)-(4-chloro-benzyl)-2(S)-hydroxy-6-
    methyl-4(R)-methylcarbamoyl-heptyl]-
    amide
    69. Quinoline-3-carboxylic acid 173.5-175   468,
    1(S)-cyclohexylmethyl-2(S)-hydroxy-7- 450
    methyl-4(R)-methylcarbamoyl-octyl)-
    amide
    70. Quinoxaline-2-carboxylic acid 78-80 470
    1(S)-cyclohexylmethyl-2(S)-hydroxy-7-
    methyl-4(R)-methylcarbamoyl-octyl)-
    amide
    71. Quinoline-3-carboxylic acid 198-201 522
    [1(S)-(4-chloro-benzyl)-5-cyclohexyl-
    2(S)-hydroxy-4(R)-methylcarbamoyl-
    pentyl]-amide
    72. Quinoxaline-2-carboxylic acid 523
    [1(S)-(4-chloro-benzyl)-5-cyclohexyl-
    2(S)-hydroxy-4(R)-methylcarbamoyl-
    pentyl]-amide
    73. Quinoline-2-carboxylic acid 522
    [1(S)-(4-chloro-benzyl)-5-cyclohexyl-
    2(S)-hydroxy-4(R)-methylcarbamoyl-
    pentyl]-amide
    74. Benzofuran-2-carboxylic acid 181-183 437
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    75. N-1(S)-Benzyl-2(S)-hydroxy-6-methyl- 195-196 466,
    4(R)-methylcarbamoyl-heptyl)-5,6- 432
    dichloro-nicotinamide
    76. Quinoline-3-carboxylic acid 188-190 462
    1(S)-benzyl-2(S)-hydroxy-7-methyl-
    4(R)-methylcarbamoyl-octyl)-amide
    77. N-1(S)-Benzyl-2(S)-hydroxy-7-methyl- 188-189 490
    4(R)-methylcarbamoyl-octyl)-5-bromo-
    nicotinamide
    78. 5,6,7,8-Tetrahydro-quinoline-3- 142.5-144.5 452
    carboxylic acid
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    79. Quinoxaline-2-carboxylic acid 147-149 463
    1(S)-benzyl-2(S)-hydroxy-7-methyl-
    4(R)-methylcarbamoyl-octyl)-amide
    80. Quinoline-2-carboxylic acid 156-158 462
    1(S)-benzyl-2(S)-hydroxy-7-methyl-
    4(R)-methylcarbamoyl-octyl)-amide,
    81. lsoquinoline-4-carboxylic acid 199-202 462
    1(S)-benzyl-2(S)-hydroxy-7-methyl-
    4(R)-methylcarbamoyl-octyl)-amide
    82. Quinoxaline-2-carboxylic acid 517,
    [1(S)-(3,4-dichloro-benzyl)-2(S)- 483
    hydroxy-6-methyl-4(R)-
    methylcarbamoyl-heptyl]-amide
    83. Benzo[b]thiophene-2-carboxylic acid 179-181 453
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    84. 2-Methyl-quinoline-3-carboxylic acid   225-226.5 462
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    85. 6,7-Dimethoxy-quinoline-3-carboxylic 211-214 508
    acid
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    86. 6,7-Difluoro-quinoline-3-carboxylic acid 187-189 484,
    1(S)-benzyl-2(S)-hydroxy-6-methyl- 466
    4(R)-methylcarbamoyl-heptyl)-amide
    87. 1H-Benzoimidazole-2-carboxylic acid 136-140 437
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    88. 5-Methyl-pyrazine-2-carboxylic acid 171.5-172.5 413
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    89. Quinoline-3-carboxylic acid 184-186 466
    [1(S)-(4-fluoro-benzyl)-2(S)-hydroxy-6-
    methyl-4(R)-methylcarbamoyl-heptyl]-
    amide
    90. Quinoxaline-2-carboxylic acid 153-156 467
    [1(S)-(4-fluoro-benzyl)-2(S)-hydroxy-6-
    methyl-4(R)-methylcarbamoyl-heptyl]-
    amide
    91. 5-Chloro-1H-indole-2-carboxylic acid 245-247 470
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    92. Quinoxaline-2-carboxylic acid   194-194.5 449,
    1(S)-benzyl-4(R)-carbamoyl-2(S)- 432
    hydroxy-7-methyl-octyl)-amide
    93. 2-Methoxy-quinoline-3-carboxylic acid 175-181 478
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide,
    94. 5,6-Dichloro-1H-benzoimidazole-2- 114-117 505
    carboxylic acid 1(S)-benzyl-2(S)-
    hydroxy-6-methyl-4(R)-
    methylcarbamoyl-heptyl)-amide
    95. Benzothiazole-2-carboxylic acid 86-89 454
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    96. 7,8-Difluoro-quinoline-3-carboxylic acid 179-182 484
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    97. 6,7,8-Trifluoro-quinoline-3-carboxylic 156-161 502,
    acid 484
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    98. 5,8-Dimethyl-quinoline-3-carboxylic 197-199 476
    acid 1(S)-benzyl-2(S)-hydroxy-6-
    methyl-4(R)-methylcarbamoyl-heptyl)-
    amide
    99. Quinoxaline-2-carboxylic acid 103-106 505
    1(S)-benzyl-4(R)-butylcarbamoyl-2(S)-
    hydroxy-7-methyl-octyl)-amide
    100. Quinoline-3-carboxylic acid 516
    [1(S)-(3,4-dichloro-benzyl)-2(S)-
    hydroxy-6-methyl-4(R)-
    methylcarbamoyl-heptyl]-amide
    101. 5,6,7,8-Tetrahydro-quinoline-3- 169.5-172.5 466
    carboxylic acid
    1(S)-benzyl-2(S)-hydroxy-7-methyl-
    4(R)-methylcarbamoyl-octyl)-amide
    102. Quinoline-3-carboxylic acid 176-178 474
    1(S)-benzyl-5-cyclopentyl-2(S)-
    hydroxy-4(R)-methylcarbamoyl-pentyl)-
    amide
    103. Quinoxaline-2-carboxylic acid 120-122 475
    1(S)-benzyl-5-cyclopentyl-2(S)-
    hydroxy-4(R)-methylcarbamoyl-pentyl)-
    amide
    104. N-1(S)-Benzyl-5-cyclopentyl-2(S)- 194-198 504
    hydroxy-4(R)-methylcarbamoyl-pentyl)-
    5-bromo-nicotinamide
    105. 5,6,7,8-Tetrahydro-quinoline-3- 143-146 478
    carboxylic acid 1(S)-benzyl-5-
    cyclopentyl-2(S)-hydroxy-4(R)-
    methylcarbamoyl-pentyl)-amide,
    106. Quinoxaline-2-carboxylic acid 217-219 461,
    1(S)-benzyl-4(R)-carbamoyl-5- 444
    cyclopentyl-2(S)-hydroxy-pentyl)-amide
    107. 6,7-Dihydro-5H-[1]pyrindine-3- 154.5-156   452,
    carboxylic acid 349
    1(S)-benzyl-2(S)-hydroxy-7-methyl-
    4(R)-methylcarbamoyl-octyl)-amide
    108. Quinoxaline-2-carboxylic acid 95-98 491,
    [1(S)-(4,4-difluoro-cyclohexylmethyl)- 473
    2(S)-hydroxy-6-methyl-4(R)-
    methylcarbamoyl-heptyl]-amide
    109. Quinoxaline-2-carboxylic acid 95-98 506,
    [1(S)-(4,4-difluoro-cyclohexylmethyl)- 488
    2(S)-hydroxy-7-methyl-4(R)-
    methylcarbamoyl-octyl]-amide
    110. Quinoxaline-2-carboxylic acid 129-133 478
    1(S)-benzyl-4(R)-ethylcarbamoyl-2(S)-
    hydroxy-7-methyl-octyl)-amide
    111. Quinoxaline-2-carboxylic acid 125-130 492
    1(S)-benzyl-2(S)-hydroxy-7-methyl-
    4(R)-propylcarbamoyl-octyl)-amide
    112. Quinoxaline-2-carboxylic acid 168-169 490,
    1(S)-benzyl-4(R)- 472
    cyclopropylcarbamoyl-2(S)-hydroxy-7-
    methyl-octyl)-amide
    113. Quinoxaline-2-carboxylic acid 148-150 504,
    1(S)-benzyl-4(R)-cyclobutylcarbamoyl- 486
    2(S)-hydroxy-7-methyl-octyl)-amide
    114. Quinoxaline-2-carboxylic acid 151-154 530
    [1(S)-(4-difluoromethoxy-benzyl)-2(S)-
    hydroxy-7-methyl-4(R)-
    methylcarbamoyl-octyl]-amide
    115. 4-{3(S)-Hydroxy-7-methyl-5(R)- 87-95 508
    methylcarbamoyl-2(S)-[(quinoxaline-
    2-carbonyl)-amino]-octyl}-benzoic acid
    methyl ester
    116. Quinoxaline-2-carboxylic acid 1(S)- 379
    benzyl-4-carbamoyl-2(S)-hydroxy-
    butyl)-amide
    117. 6,7,8-Trifluoro-quinoline-3-carboxylic 206-207 516,
    acid 498
    1(S)-benzyl-2(S)-hydroxy-7-methyl-
    4(R)-methylcarbamoyl-octyl)-amide
    118. 6,7,8-Trifluoro-quinoline-3-carboxylic 205-206 502,
    acid 485
    1(S)-benzyl-4(R)-carbamoyl-2(S)-
    hydroxy-7-methyl-octyl)-amide
    119. 6,8-Difluoro-quinoline-3-carboxylic acid 198-200 498
    1(S)-benzyl-2(S)-hydroxy-7-methyl-
    4(R)-methylcarbamoyl-octyl)-amide
    120. 6,8-Difluoro-quinoline-3-carboxylic acid 188-190 484,
    1(S)-benzyl-4(R)-carbamoyl-2(S)- 467
    hydroxy-7-methyl-octyl)-amide
    121. Quinoxaline-2-carboxylic acid 102-104 517,
    1(S)-benzyl-4(R)-butylcarbamoyl-5- 499
    cyclopentyl-2(S)-hydroxy-pentyl)-amide
    122. 6-Methyl-pyridine-2-carboxylic acid 74-76
    1(S)-benzyl-2(S)-hydroxy-6-methyl-
    4(R)-methylcarbamoyl-heptyl)-amide
    123. Quinoxaline-2-carboxylic acid 145.5-146.5 477
    1(S)-benzyl-2(S)-hydroxy-8-methyl-
    4(R)-methylcarbamoyl-nonyl)-amide
    124. Quinoxaline-2-carboxylic acid 163-165 463
    1(S)-benzyl-4(R)-carbamoyl-2(S)-
    hydroxy-8-methyl-nonyl)-amide
    125. Quinoxaline-2-carboxylic acid 123-125 539,
    1(S)-biphenyl-4-ylmethyl-2(S)-hydroxy- 521,
    7-methyl-4(R)-methylcarbamoyl-octyl)- 508
    amide
    126. Quinoxaline-2-carboxylic acid 168-170 447,
    1(S)-benzyl-4(R)-carbamoyl-2(S)- 430
    hydroxy-7-methyl-oct-6-enyl)-amide
    127. Quinoxaline-2-carboxylic acid 121-123
    (2(S)-hydroxy-6-methyl-4(R)-
    methylcarbamoyl-1(S)-naphthalen-2-
    ylmethyl-heptyl)-amide
    128. Quinoxaline-2-carboxylic acid 77-79 463,
    1(S)-benzyl-4(R)-carbamoyl-2(S)- 446
    hydroxy-7,7-dimethyl-octyl)-amide
    129. Quinoxaline-2-carboxylic acid 195-199 477,
    1(S)-benzyl-2(S)-hydroxy-7,7-dimethyl- 459
    4(R)-methylcarbamoyl-octyl)-amide
    130. Quinoxaline-2-carboxylic acid 168-172 469,
    1(S)-benzyl-4(R)-carbamoyl-2(S)- 452
    hydroxy-5-phenyl-pentyl)-amide
    131. Quinoxaline-2-carboxylic acid 205-206 508
    1(S)-biphenyl-4-ylmethyl-4(R)-
    carbamoyl-2(S)-hydroxy-7-methyl-
    octyl)-amide
    132. Quinoxaline-2-carboxylic acid 170-172 525,
    [1(S)-benzyl-5-(4,4-difluoro- 507
    cyclohexyl)-2(S)-hydroxy-4(R)-
    methylcarbamoyl-pentyl]-amide
    133. Quinoxaline-2-carboxylic acid 174-176 511,
    [1(S)-benzyl-4(R)-carbamoyl-5-(4,4- 493
    difluoro-cyclohexyl)-2(S)-hydroxy-
    pentyl]-amide
    134. Quinoxaline-2-carboxylic acid 158.5-159.5 481,
    [1(S)-(3-fluoro-benzyl)-2(S)-hydroxy-7- 463
    methyl-4(R)-methylcarbamoyl-octyl]-
    amide
    135. Quinoxaline-2-carboxylic acid   191-191.5 467,
    [4(R)-carbamoyl-1(S)-(3-fluoro-benzyl)- 449
    2(S)-hydroxy-7-methyl-octyl]-amide
    136. Quinoxaline-2-carboxylic acid 65-68 461,
    1(S)-benzyl-2(S)-hydroxy-7-methyl- 443
    4(R)-methylcarbamoyl-oct-6-enyl)-
    amide
    137. 6,7,8-Trifluoro-quinoline-3-carboxylic 158-161 541,
    acid 1(S)-benzyl-2(S)-hydroxy-7(S)- 523
    methyl-4(R)-methylcarbamoyl-nonyl)-
    amide
    138. Quinoxaline-2-carboxylic acid 185-187 446
    1(S)-benzyl-4(R)-carbamoyl-2(S)-
    hydroxy-7(S)-methyl-nonyl)-amide
    139. Quinoxaline-2-carboxylic acid 148-150 482,
    1(S)-benzyl-7-fluoro-2(S)-hydroxy-7- 463
    methyl-4(R)-methylcarbamoyl-octyl)-
    amide
    140. Quinoxaline-2-carboxylic acid 184-186 467,
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro- 449
    2(S)-hydroxy-7-methyl-octyl)-amide
    141. Quinoxaline-2-carboxylic acid   137-139.5 478
    1(S)-benzyl-2(S)-hydroxy-7-methyl-
    4(R)-methylcarbamoyl-nonyl)-amide
    142. Quinoxaline-2-carboxylic acid 68-70
    1(S)-benzyl-4(R)-dimethylcarbamoyl-
    2(S)-hydroxy-7-methyl-octyl)-amide
    143. 7,8-Difluoro-quinoline-3-carboxylic acid 175 518,
    1(S)-benzyl-2(S)-hydroxy-4(R)- (Dec.) 500
    methylcarbamoyl-5-phenyl-pentyl)-
    amide
    144. 7,8-Difluoro-quinoline-3-carboxylic acid 198-201 498,
    1(S)-benzyl-2(S)-hydroxy-7-methyl- 480
    4(R)-methylcarbamoyl-octyl)-amide
    145. 8-Fluoro-quinoline-3-carboxylic acid 179-183 480,
    1(S)-benzyl-2(S)-hydroxy-7-methyl- 462
    4(R)-methylcarbamoyl-octyl)-amide
    146. Quinoxaline-2-carboxylic acid 130-132 462,
    1(S)-benzyl-2(S)-hydroxy-4(R)- 448
    methylcarbamoyl-non-6-enyl)-amide
    147. Quinoxaline-2-carboxylic acid 154-155 448,
    1(S)-benzyl-4(R)-carbamoyl-2(S)- 430
    hydroxy-non-6-enyl)-amide
    148. 7,8-Difluoro-quinoline-3-carboxylic acid 188-190 485,
    1(S)-benzyl-4(R)-carbamoyl-2(S)- 467
    hydroxy-7-methyl-octyl)-amide
    149. 8-Fluoro-quinoline-3-carboxylic acid 192-196 466,
    1(S)-benzyl-4(R)-carbamoyl-2(S)- 449
    hydroxy-7-methyl-octyl)-amide
    150. Quinoxaline-2-carboxylic acid 188.5-189.5 450
    1(S)-benzyl-4(R)-carbamoyl-2(S)-
    hydroxy-nonyl)-amide
    151. 2(S)-{2(S)-hydroxy-4-phenyl-3(S)- 178-180
    [(quinoxaline-2-carbonyl)-amino]-butyl}-
    N1,N4-dimethyl-succinamide
    152. Quinoxaline-2-carboxylic acid 105-108 496
    1(S)-benzyl-4(R)-ethylcarbamoyl-7-
    fluoro-2(S)-hydroxy-7-methyl-octyl)-
    amide
    153. Quinoxaline-2-carboxylic acid 110-112 523,
    1(S)-benzyl-4(R)-butylcarbamoyl-7- 505
    fluoro-2(S)-hydroxy-7-methyl-octyl)-
    amide
    154. Quinoxaline-2-carboxylic acid 145-147 499
    [7-fluoro-1(S)-(4-fluoro-benzyl)-2(S)-
    hydroxy-7-methyl-4(R)-
    methylcarbamoyl-octyl]-amide
    155. Quinoxaline-2-carboxylic acid 206-207 536,
    [4(R)-carbamoyl-1(S)-(3,4-dichloro- 518
    benzyl)-7-fluoro-2(S)-hydroxy-7-methyl-
    octyl]-amide
    156. 7,8-Difluoro-quinoline-3-carboxylic acid 187-189 571
    [4(R)-carbamoyl-1(S)-(3,4-dichloro-
    benzyl)-7-fluoro-2(S)-hydroxy-7-methyl-
    octyl]-amide
    157. Quinoxaline-2-carboxylic acid 223-225 478
    (4(R)-carbamoyl-2(S)-hydroxy-7-
    methyl-1(S)-phenethyl-octyl)-amide,
    158. 7,8-Difluoro-quinoline-3-carboxylic acid 208-210 463,
    [4(R)-carbamoyl-7-fluoro-1(S)-(4- 445
    fluoro-benzyl)-2(S)-hydroxy-7-methyl-
    octyl]-amide
    159. Quinoxaline-2-carboxylic acid 520
    [4(R)-carbamoyl-7-fluoro-1(S)-(4-
    fluoro-benzyl)-2(S)-hydroxy-7-methyl-
    octyl]-amide
    160. Quinoxaline-2-carboxylic acid 551
    [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-
    methyl-4(R)-(4-methyl-piperazine-1-
    carbonyl)-octyl]-amide,
    161. Quinoxaline-2-carboxylic acid 212-214 477,
    [1(S)-benzyl-4(R)-carbamoyl-2(S)- 459
    hydroxy-5-(tetrahydro-pyran-4(R)-yl)-
    pentyl]-amide
    162. Quinoxaline-2-carboxylic acid 536
    [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-
    methyl-4(R)-(piperidine-1-carbonyl)-
    octyl]-amide
    163. Quinoxaline-2-carboxylic acid 537
    [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-
    methyl-4(R)-(morpholine-4-carbonyl)-
    octyl]-amide,
    164. Quinoxaline-2-carboxylic acid 90-100 481,
    [1(S)-benzyl-3-(2-carbamoyl-indan-2- 464
    yl)-2(S)-hydroxy-propyl]-amide
    165. Quinoxaline-2-carboxylic acid 212-216
    1(S)-benzyl-2(S)-hydroxy-4(R)- (Dec.)
    methylcarbamoyl-7-phenyl-hept-6-
    enyl)-amide
    166. Quinoline-2-carboxylic acid 163.5-165   466,
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro- 449
    2(S)-hydroxy-7-methyl-octyl)-amide
    167. 6,7-Dihydro-5H-[1]pyrindine-3- 175-178 456
    carboxylic acid
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro-
    2(S)-hydroxy-7-methyl-octyl)-amide
    168. Quinoxaline-2-carboxylic acid (1(S)- 222-223 461,
    benzyl-4-carbamoyl-4(S)-cyclohexyl- 444
    2(S)-hydroxy-butyl)-amide;
    169. Quinoxaline-2-carboxylic acid (1(S)- 178-180 461,
    benzyl-4-carbamoyl-4(S)-cyclohexyl- 444
    2(S)-hydroxy-butyl)-amide
    170. Quinoxaline-2-carboxylic acid (1(S)- 229-232 447
    benzyl-4-carbamoyl-4(S)-cyclohexyl-
    2(S)-hydroxy-butyl)-amide
    171. Quinoxaline-2-carboxylic acid (1(S)- 126-128 447
    benzyl-4-carbamoyl-4(S)-cyclopentyl-
    2(S)-hydroxy-butyl)-amide;
    172. Quinoline-3-carboxylic acid 200-202 466,
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro- 449
    2(S)-hydroxy-7-methyl-octyl)-amide
    173. N-1(S)-Benzyl-4(R)-carbamoyl-7- 181-183 476
    fluoro-2(S)-hydroxy-7-methyl-octyl)-5-
    bromo-nicotinamide
    174. Quinoxaline-2-carboxylic acid 184-187 466,
    [4(R)-carbamoyl-1-(2(S)-fluoro-benzyl)- 448
    2(S)-hydroxy-7-methyl-octyl]-amide
    175. Quinoxaline-2-carboxylic acid 213-215 466
    [4(R)-carbamoyl-1(S)-(2-fluoro-benzyl)-
    2(S)-hydroxy-7-methyl-octyl]-amide
    176. Quinoxaline-2-carboxylic acid [1(S)- 502
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-
    (4-isopropyl-cyclohexyl)-butyl]-amide;
    177. Quinoxaline-2-carboxylic acid 454,
    (4(R)-carbamoyl-2(S)-hydroxy-7- 436
    methyl-1(S)-thiophen-2-ylmethyl-octyl)-
    amide
    178. Quinoxaline-2-carboxylic acid 195-196 456
    (4(R)-carbamoyl-2(S)-hydroxy-7-
    methyl-1(S)-thiazol-4-ylmethyl-octyl)-
    amide
    179. Quinoxaline-2-carboxylic acid [1(S)- 188-190 516
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-
    (3,3,5,5-tetramethyl-cyclohexyl)-butyl]-
    amide
    180. Quinoxaline-2-carboxylic acid (1(S)- 495
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-
    indan-2-yl-butyl)-amide;
    181. Quinoxaline-2-carboxylic acid (1(S)- 216-217 474,
    benzyl-4(S)-carbamoyl-4-cycloheptyl- 457
    2(S)-hydroxy-butyl)-amide;
    182. Quinoxaline-2-carboxylic acid (1(S)- 477
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-5-
    propyl-octyl)-amide;
    183. Quinoxaline-2-carboxylic acid (1(S)-
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-5-
    propyl-oct-5-enyl)-amide;
    184. Quinoxaline-2-carboxylic acid
    1(S)-benzyl-4(R)-carbamoyl-2(S),7-
    dihydroxy-7-methyl-octyl)-amide
    185. Quinoxaline-2-carboxylic acid 467,
    1(S)-benzyl-7-chloro-2(S)-hydroxy- 449
    4(R)-methylcarbamoyl-hept-6-enyl)-
    amide
    186. Quinoxaline-2-carboxylic acid 467,
    1(S)-benzyl-7-chloro-2(S)-hydroxy- 449
    4(R)-methylcarbamoyl-hept-6-enyl)-
    amide
    187. Quinoxaline-2-carboxylic acid 160-162 467,
    1(S)-benzyl-6-chloro-2(S)-hydroxy- 449
    4(S)-methylcarbamoyl-hept-6-enyl)-
    amide
    188. Quinoxaline-2-carboxylic acid   203-204.5
    1(S)-benzyl-4(R)-carbamoyl-6-chloro-
    2(S)-hydroxy-hept-6-enyl)-amide
    189. Quinoxaline-2-carboxylic acid 171-174 447,
    1(S)-benzyl-4(S)-carbamoyl-6- 429
    cyclopropyl-2(S)-hydroxy-hexyl)-amide
    190. Quinoxaline-2-carboxylic acid 146-148 461,
    1(S)-benzyl-6-cyclopropyl-2(S)- 443
    hydroxy-4(R)-methylcarbamoyl-hexyl)-
    amide
    191. Quinoxaline-2-carboxylic acid [1(S)- 218-220 475,
    benzyl-4(R)-carbamoyl-2(S)-hydroxy- 457
    4(S)-(4-methyl-cyclohexyl)-butyl]-
    amide;
    192. Quinoxaline-2-carboxylic acid (1(S)- 190-191 495,
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4- 477
    indan-2-yl-butyl)-amide;
    193. Quinoxaline-2-carboxylic acid 184-187 553,
    [1(S)-benzyl-4(R)-carbamoyl-2(S)- 536
    hydroxy-5-(4-trifluoromethoxy-phenyl)-
    pentyl]-amide
    194. Quinoxaline-2-carboxylic acid 164-166 487,
    [1(S)-benzyl-4(R)-carbamoyl-5-(4- 470
    fluoro-phenyl)-2(S)-hydroxy-pentyl]-
    amide
    195. Quinoxaline-2-carboxylic acid 165-166 436
    1(S)-benzyl-4(R)-carbamoyl-7-chloro-
    2(S)-hydroxy-hept-6-enyl)-amide
    196. Quinoxaline-2-carboxylic acid 158-160 436
    1(S)-benzyl-4(R)-carbamoyl-7-chloro-
    2(S)-hydroxy-hept-6-enyl)-amide
    197. 3-Hydroxy-quinoxaline-2-carboxylic 185-189 483,
    acid 1(S)-benzyl-4(R)-carbamoyl-7- 465
    fluoro-2(S)-hydroxy-7-methyl-octyl)-
    amide
    198. Quinoxaline-2-carboxylic acid 183-184
    1(S)-benzyl-4(R)-benzylcarbamoyl-7-
    fluoro-2(S)-hydroxy-7-methyl-octyl)-
    amide
    199. Quinoxaline-2-carboxylic acid 188-191
    {1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-
    methyl-4(R)-[(pyridin-3-ylmethyl)-
    carbamoyl]-octyl}-amide
    200. Quinoxaline-2-carboxylic acid 571,
    1(S)-benzyl-8,8-trifluoro-2(S)-hydroxy- 553
    4(R)-methylcarbamoyl-7-
    trifluoromethyl-octyl)-amide
    201. Quinoxaline-2-carboxylic acid 187-193 553
    1(S)-benzyl-4(R)-carbamoyl-8,8-
    trifluoro-2(S)-hydroxy-7-trifluoromethyl-
    octyl)-amide
    202. Quinoxaline-2-carboxylic acid 170-173 502
    [2(S)-hydroxy-7-methyl-4(R)-
    methylcarbamoyl-1(S)-(4-
    methylcarbamoyl-benzyl)-octyl]-amide
    203. Quinoxaline-2-carboxylic acid (1(S)- 215-218 448,
    benzyl-4(S)-carbamoyl-5-ethyl-2(S)- 431
    hydroxy-heptyl)-amide;
    204. Quinoxaline-2-carboxylic acid [1(S)- 151-154
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-
    (tetrahydro-pyran-4-yl)-butyl]-amide;
    205. Quinoxaline-2-carboxylic acid 155-156 572
    [1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-
    methyl-4(R)-(2-pyridin-2-yl-
    ethylcarbamoyl)-octyl]-amide
    206. Quinoxaline-2-carboxylic acid 162-164 617
    [1(S)-benzyl-4(R)-(3,4-dimethoxy-
    benzylcarbamoyl)-7-fluoro-2(S)-
    hydroxy-7-methyl-octyl]-amide
    207. Quinoxaline-2-carboxylic acid 1(S)- 420
    benzyl-4(R)-carbamoyl-2(S)-hydroxy-6-
    methoxy-hexyl)-amide
    208. Quinoxaline-2-carboxylic acid 172-175 450
    1(S)-benzyl-4(R)-carbamoyl-7-chloro-
    2(S)-hydroxy-oct-6-enyl)-amide
    209. Quinoxaline-2-carboxylic acid 108-111 463
    1(S)-benzyl-7-chloro-2(S)-hydroxy-
    4(R)-methylcarbamoyl-oct-6-enyl)-
    amide
    210. Quinoxaline-2-carboxylic acid [1(S)- 221-222 489,
    benzyl-4(R)-carbamoyl-4-(3,5-dimethyl- 471
    cyclohexyl)-2(S)-hydroxy-butyl]-amide;
    211. Quinoxaline-2-carboxylic acid {1(S)- 138-140 557,
    benzyl-7-fluoro-2(S)-hydroxy-7-methyl- 540
    4(R)-[(pyridin-2-ylmethyl)-carbamoyl]-
    octyl}-amide
    212. Quinoxaline-2-carboxylic acid {1(S)- 138-140 587,
    benzyl-7-fluoro-2(S)-hydroxy-4(R)-[2- 569
    (4-hydroxy-phenyl)-ethylcarbamoyl]-7-
    methyl-octyl}-amide
    213. Quinoxaline-2-carboxylic acid {1(S)- 174-175 563,
    benzyl-7-fluoro-2(S)-hydroxy-7-methyl- 545
    4(R)-[(thiophen-2-ylmethyl)-
    carbamoyl]-octyl}-amide
    214. Quinoxaline-2-carboxylic acid 194.5-196.5 482
    1(S)-benzyl-4(R)-carbamoyl-2(S)-
    hydroxy-6-phenoxy-hexyl)-amide
    215. Quinoxaline-2-carboxylic acid 113-118 448
    1(S)-benzyl-4(R)-carbamoyl-2(S)- (Mix)
    hydroxy-6-isopropoxy-hexyl)-amide
    216. Quinoxaline-2-carboxylic acid {1(S)- 207-210 650
    benzyl-7-fluoro-2(S)-hydroxy-7-methyl-
    4(R)-[2-(4-sulfamoyl-phenyl)-
    ethylcarbamoyl]-octyl}-amide
    217. Quinoxaline-2-carboxylic acid {1(S)- 100-104 558
    benzyl-7-fluoro-2(S)-hydroxy-7-methyl-
    4(R)-[(pyridin-4-ylmethyl)-carbamoyl]-
    octyl}-amide
    218. Quinoxaline-2-carboxylic acid [1(S)- 78-79 555,
    benzyl-4(R)-(2-ethylsulfanyl- 537
    ethylcarbamoyl)-7-fluoro-2(S)-hydroxy-
    7-methyl-octyl]-amide
    219. Quinoxaline-2-carboxylic acid [1(S)- 48-50 507
    benzyl-7-fluoro-2(S)-hydroxy-4(R)-(2-
    methoxy-ethylcarbamoyl)-7-methyl-
    octyl]-amide
    220. Quinoxaline-2-carboxylic acid [1(S)- 154-155 572
    benzyl-7-fluoro-2(S)-hydroxy-7-methyl-
    4(R)-(2-pyridin-3-yl-ethylcarbamoyl)-
    octyl]-amide
    221. Quinoxaline-2-carboxylic acid [1(S)- 78-80 572
    benzyl-7-fluoro-2(S)-hydroxy-7-methyl-
    4(R)-(2-pyridin-4-yl-ethylcarbamoyl)-
    octyl]-amide
    222. Quinoxaline-6-carboxylic acid 190-192 467
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro-
    2(S)-hydroxy-7-methyl-octyl)-amide
    223. Quinoxaline-2-carboxylic acid 184-189 479,
    1(S)-benzyl-6-tert-butoxy-4(R)- 461
    carbamoyl-2(S)-hydroxy-hexyl)-amide
    224. Quinoxaline-2-carboxylic acid {1(S)- 100-105 574
    benzyl-7-fluoro-2(S)-hydroxy-7-methyl-
    4(R)-[2-1-methyl-1H-pyrrol-2-yl)-
    ethylcarbamoyl]-octyl}-amide
    225. Quinoxaline-2-carboxylic acid [1(S)- 140-150 511,
    benzyl-4(S)-carbamoyl-4-(1,1-dioxo- 494
    thiopyran-4-yl)-2(S)-hydroxy-butyl]-
    amide;
    226. Quinoxaline-2-carboxylic acid {1(S)- 640,
    benzyl-7-fluoro-2(S)-hydroxy-4(R)-[2- 622
    (6-methoxy-1H-indol-3-yl)-
    ethylcarbamoyl]-7-methyl-octyl}-amide,
    227. Quinoxaline-2-carboxylic acid 135 587,
    [1(S)-benzyl-7-fluoro-2(S)-hydroxy- 569
    4(R)-(2-methoxy-benzylcarbamoyl)-7-
    methyl-octyl]-amide
    228. Quinoxaline-2-carboxylic acid 587,
    [1(S)-benzyl-7-fluoro-2(S)-hydroxy- 569
    4(R)-(3-methoxy-benzylcarbamoyl)-7-
    methyl-octyl]-amide
    229. Quinoxaline-2-carboxylic acid [1(S)- 152-154 577
    benzyl-7-fluoro-2(S)-hydroxy-7-methyl-
    4(R)-(2-thiophen-2-yl-ethylcarbamoyl)-
    octyl]-amide
    230. Quinoxaline-2-carboxylic acid {1(S)- 107-108 610
    benzyl-7-fluoro-2(S)-hydroxy-4(R)-[2-
    (1H-indol-3-yl)-ethylcarbamoyl]-7-
    methyl-octyl}-amide
    231. Quinoxaline-2-carboxylic acid {4(R)-[2- 586
    (4-amino-phenyl)-ethylcarbamoyl]-1(S)-
    benzyl-7-fluoro-2(S)-hydroxy-7-methyl-
    octyl}-amide
    232. Quinoxaline-2-carboxylic acid {1(S)- 109-112 631,
    benzyl-4(R)-[2-(3,5-dimethoxy-phenyl)- 613
    ethylcarbamoyl]-7-fluoro-2(S)-hydroxy-
    7-methyl-octyl}-amide
    233. Quinoxaline-2-carboxylic acid {1(S)- 631,
    benzyl-4(R)-[2-(3,4-dimethoxy-phenyl)- 613
    ethylcarbamoyl]-7-fluoro-2(S)-hydroxy-
    7-methyl-octyl}-amide
    234. Quinoxaline-2-carboxylic acid {1(S)- 155.5-156.5 547
    benzyl-7-fluoro-4(R)-[(furan-2-
    ylmethyl)-carbamoyl]-2(S)-hydroxy-7-
    methyl-octyl}-amide
    235. Quinoxaline-2-carboxylic acid {1(S)- 631,
    benzyl-4(R)-[2-(2,5-dimethoxy-phenyl)- 613
    ethylcarbamoyl]-7-fluoro-2(S)-hydroxy-
    7-methyl-octyl}-amide
    236. Quinoxaline-2-carboxylic acid 114-115 587,
    [1(S)-benzyl-7-fluoro-2(S)-hydroxy- 569
    4(R)-(4-methoxy-benzylcarbamoyl)-7-
    methyl-octyl]-amide
    237. Quinoxaline-2-carboxylic acid 150-152 505,
    1(S)-benzyl-4(R)-carbamoyl-6- 487
    cyclohexyloxy-2(S)-hydroxy-hexyl)-
    amide
    238. Quinoxaline-2-carboxylic acid {4(R)- 596
    [(1H-benzoimidazol-2-ylmethyl)-
    carbamoyl]-1(S)-benzyl-7-fluoro-2(S)-
    hydroxy-7-methyl-octyl}-amide
    239. Quinoxaline-2-carboxylic acid [1(S)- 217-219 551,
    benzyl-7-fluoro-2(S)-hydroxy-4(R)- 533
    (2(S)-hydroxymethyl-pyrrolidine-1-
    carbonyl)-7-methyl-octyl]-amide
    240. Quinoxaline-2-carboxylic acid {1(S)- 111-115 551,
    benzyl-7-fluoro-2(S)-hydroxy-7-methyl- 533
    4(R)-[(tetrahydrofuran-2-ylmethyl)-
    carbamoyl]-octyl}-amide
    241. Quinoxaline-2-carboxylic acid [1(S)- 176-179 497,
    benzyl-4(S)-carbamoyl-4-(4,4-difluoro- 478
    cyclohexyl)-2(S)-hydroxy-butyl]-amide
    242. Quinoxaline-2-carboxylic acid 99-101
    [1(S)-benzyl-4(R)-(2,3-dimethoxy-
    benzylcarbamoyl)-7-fluoro-2(S)-
    hydroxy-7-methyl-octyl]-amide
    243. Quinoxaline-2-carboxylic acid [1(S)- 187-189 477,
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4- 379
    (1-hydroxy-cyclohexyl)-butyl]-amide;
    244. Quinoxaline-2-carboxylic acid [1(S)- 195-198 491
    benzyl-4(S)-carbamoyl-4-(2,6-dimethyl-
    tetrahydro-pyran-4-yl)-2(S)-hydroxy-
    butyl]-amide;
    245. Quinoxaline-2-carboxylic acid 225-227 485,
    [4(R)-carbamoyl-7-fluoro-1(S)-(3- 467
    fluoro-benzyl)-2(S)-hydroxy-7-methyl-
    octyl]-amide
    246. 7,8-Difluoro-quinoline-3-carboxylic acid >220   502,
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro- 485
    2(S)-hydroxy-7-methyl-octyl)-amide
    247. N-1(S)-Benzyl-4(R)-carbamoyl-7- >220   484,
    fluoro-2(S)-hydroxy-7-methyl-octyl)- 466
    5,6-dichloro-nicotinamide
    248. Benzofuran-2-carboxylic acid 1(S)- 190-192 455,
    benzyl-4(R)-carbamoyl-7-fluoro-2(S)- 438
    hydroxy-7-methyl-octyl)-amide
    249. Cinnoline-4-carboxylic acid 1(S)-   198-199.5 469,
    benzyl-4(R)-carbamoyl-7-fluoro-2(S)- 451
    hydroxy-7-methyl-octyl)-amide
    250. Quinoxaline-2-carboxylic acid 185.5-187.5 593,
    [4(R)-carbamoyl-7-fluoro-2(S)-hydroxy- 576
    1(S)-(4-iodo-benzyl)-7-methyl-octyl]-
    amide,
    251. Pyrazine-2-carboxylic acid 211-212 417,
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro- 319
    2(S)-hydroxy-7-methyl-octyl)-amide,
    252. 6,7,8-Trifluoro-quinoline-3-carboxylic 195-197 520,
    acid 503
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro-
    2(S)-hydroxy-7-methyl-octyl)-amide,
    253. Quinoline-6-carboxylic acid 170-173 466,
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro- 449
    2(S)-hydroxy-7-methyl-octyl)-amide,
    254. Isoquinoline-3-carboxylic acid 194-197 466,
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro- 448
    2(S)-hydroxy-7-methyl-octyl)-amide,
    255. 2-Methoxy-quinoline-3-carboxylic acid 213-216 496,
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro- 479
    2(S)-hydroxy-7-methyl-octyl)-amide,
    256. 1H-Benzoimidazole-2-carboxylic acid 168-169 456,
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro- 438
    2(S)-hydroxy-7-methyl-octyl)-amide,
    257. Benzothiazole-2-carboxylic acid 152.5-155   472,
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro- 455
    2(S)-hydroxy-7-methyl-octyl)-amide
    258. 5-Methyl-pyrazine-2-carboxylic acid 194-197 431
    1(S)-benzyl-4(R)-carbamoyl-7-fluoro-
    2(S)-hydroxy-7-methyl-octyl)-amide
    259. Quinoxaline-2-carboxylic acid 470,
    1(S)-benzyl-4(R)-carbamoyl-2(S)- 453
    hydroxy-5-pyridin-3-yl-pentyl)-amide
    260. Quinoxaline-2-carboxylic acid [1(S)- 210-211 477,
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4- 459
    (1-hydroxy-cyclohexyl)-butyl]-amide;
    261. Quinoline-3-carboxylic acid (1(S)- 231 460,
    benzyl-4(S)-carbamoyl-4-cyclohexyl- 443
    2(S)-hydroxy-butyl)-amide
    262. Quinoline-2-carboxylic acid (1(S)- 208-210 460,
    benzyl-4(S)-carbamoyl-4-cyclohexyl- 443
    2(S)-hydroxy-butyl)-amide
    263. Fluoro-quinoline-3-carboxylic acid 238-240 478,
    (1(S)-benzyl-4(S)-carbamoyl-4- 461
    cyclohexyl-2(S)-hydroxy-butyl)-amide
    264. N-(1(S)-Benzyl-4(S)-carbamoyl-4- 174-177 461
    cyclohexyl-2(S)-hydroxy-butyl)-5,6-
    dichloro-nicotinamide;
    265. N-(1(S)-Benzyl-4(S)-carbamoyl-4- 255-256 475,
    cyclohexyl-2(S)-hydroxy-butyl)-5- 458
    bromo-nicotinamide;
    266. Quinoxaline-2-carboxylic acid   159-160.5 453
    (4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-
    7-methyl-1(S)-phenyl-octyl)-amide,
    267. Quinoxaline-2-carboxylic acid 470,
    1(S)-benzyl-4(R)-carbamoyl-2(S)- 453
    hydroxy-5-pyridin-2-yl-pentyl)-amide,
    268. Quinoxaline-2-carboxylic acid [4(R)- 206-207 482
    carbamoyl-2(S)-hydroxy-4-(1-hydroxy-
    cyclohexyl)-1(S)-thiophen-2-ylmethyl-
    butyl]-amide;
    269. Quinoxaline-2-carboxylic acid [1(S)- 123-125 495,
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4- 379
    (4-hydroxy-tetrahydro-thiopyran-4-yl)-
    butyl]-amide;
    270. 1,3-Dimethyl-1H-pyrazolo[3,4- 189.5-191   484,
    b]pyridine-5-carboxylic acid 1(S)- 467
    benzyl-4(R)-carbamoyl-7-fluoro-2(S)-
    hydroxy-7-methyl-octyl)-amide,
    271. Quinoxaline-2-carboxylic acid (1(S)- 165-166
    benzyl-7-fluoro-2(S)-hydroxy-4(R)-
    hydroxycarbamoyl-7-methyl-octyl)-
    amide
    272. Quinoxaline-2-carboxylic acid (1(S)-
    benzyl-7-fluoro-2(S)-hydroxy-4(R)-
    methoxycarbamoyl-7-methyl-octyl)-
    amide
    273. 7,8-Difluoro-quinoline-3-carboxylic acid 233-235
    (1(S)-benzyl-4(R)-carbamoyl-2(S)-
    hydroxy-5-phenyl-pentyl)-amide
    274. Quinoxaline-2-carboxylic acid [1(S)- 182-185
    benzyl-4(R)-carbamoyl-5-(2-chloro-
    phenyl)-2(S)-hydroxy-pentyl]-amide
    275. Quinoxaline-2-carboxylic acid (1(S)- 168-171
    benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-
    o-tolyl-pentyl)-amide
    276. Quinoxaline-2-carboxylic acid (1(S)- 190-192
    benzyl-2(S)-hydroxy-4(R)-
    hydroxycarbamoyl-5-phenyl-pentyl)-
    amide
    277. Quinoxaline-2-carboxylic acid [1(S)- 192-195 463,
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4- 446
    (1-hydroxy-cyclopentyl)-butyl]-amide
    278. Quinoxaline-2-carboxylic acid [1(S)- 230-233 490
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-
    (1-hydroxy-4-methyl-cyclohexyl)-butyl]-
    amide
    279. Quinoxaline-2-carboxylic acid [1(S)- 199-201
    benzyl-4(S)-carbamoyl-5-(3,4-dichloro-
    phenyl)-2(S)-hydroxy-pentyl]-amide
    280. Quinoxaline-2-carboxylic acid [1(S)- 171-173
    benzyl-4(R)-carbamoyl-5-(2-fluoro-
    phenyl)-2(S)-hydroxy-pentyl]-amide
    281. Quinoxaline-2-carboxylic acid [1(S)- 110-112 477
    benzyl-2(S)-hydroxy-4(S)-
    hydroxycarbamoyl-4-(1-hydroxy-
    cyclopentyl)-butyl]-amide
    282. Quinoxaline-2-carboxylic acid [1(S)- 187-188 476
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-
    (1-hydroxy-3-methyl-cyclopentyl)-butyl]-
    amide
    283. Quinoxaline-2-carboxylic acid [1(S)- 114-116 506
    benzyl-2(S)-hydroxy-4(S)-
    hydroxycarbamoyl-4-(1-hydroxy-4-
    methyl-cyclohexyl)-butyl]-amide
    284. N-(1(S)-Benzyl-4(R)-carbamoyl-2(S)- 494,
    hydroxy-5-phenyl-pentyl)-5-bromo- 496
    nicotinamide
    285. 8-Fluoro-quinoline-3-carboxylic acid 206-209
    (1(S)-benzyl-4(R)-carbamoyl-2(S)-
    hydroxy-5-phenyl-pentyl)-amide
    286. 6,7-Dihydro-5H-[1]pyrindine-3- 182-186
    carboxylic acid (1(S)-benzyl-4(R)-
    carbamoyl-2(S)-hydroxy-5-phenyl-
    pentyl)-amide
    287. Quinoline-3-carboxylic acid (1(S)- 203-206
    benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-
    phenyl-pentyl)-amide
    288. Quinoxaline-2-carboxylic acid [1(S)- 234-236 504
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-
    (1-hydroxy-3,5-dimethyl-cyclohexyl)-
    butyl]-amide
    289. Quinoxaline-2-carboxylic acid [1(S)- 520
    benzyl-2(S)-hydroxy-4(S)-
    hydroxycarbamoyl-4-(1-hydroxy-3,5-
    dimethyl-cyclohexyl)-butyl]-amide
    290. Quinoxaline-2-carboxylic acid [1(S)- 189-191 491
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-
    (1-hydroxy-cycloheptyl)-butyl]-amide
    291. Quinoxaline-2-carboxylic acid [1(S)- 118-119 506
    benzyl-2(S)-hydroxy-4(S)-
    hydroxycarbamoyl-4-(1-hydroxy-
    cycloheptyl)-butyl]-amide
    292. Quinoxaline-2-carboxylic acid [1(S)- 176-179
    benzyl-4(R)-carbamoyl-5-(3-fluoro-
    phenyl)-2(S)-hydroxy-pentyl]-amide
    293. Quinoxaline-2-carboxylic acid (1(S)- 178-179
    benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-
    m-tolyl-pentyl)-amide
    294. Quinoxaline-2-carboxylic acid (1(S)- 146-148
    benzyl-2(S)-hydroxy-4-
    isobutylcarbamoyl-butyl)-amide
    295. Quinoxaline-2-carboxylic acid [1(S)- 206-207 528
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-
    (2-hydroxy-adamantan-2-yl)-butyl]-
    amide
    296. Quinoxaline-2-carboxylic acid [1(S)- 268-269 516
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-
    (9-hydroxy-bicyclo[3.3.1]non-9-yl)-
    butyl]-amide
    297. Quinoxaline-2-carboxylic acid [1(S)- 133-134 544
    benzyl-2(S)-hydroxy-4(S)-(2-hydroxy-
    adamantan-2-yl)-4-hydroxycarbamoyl-
    butyl]-amide
    298. Quinoxaline-2-carboxylic acid [1(S)- 130-132 532
    benzyl-2(S)-hydroxy-4(S)-(9-hydroxy-
    bicyclo[3.3.1]non-9-yl)-4-
    hydroxycarbamoyl-butyl]-amide
    299. Quinoxaline-2-carboxylic acid [1(S)- 147-148
    benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-
    (3-methoxy-phenyl)-pentyl]-amide
    300. Quinoxaline-2-carboxylic acid [1(S)- 227-228 519
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-
    (1-hydroxy-4-propyl-cyclohexyl)-butyl]-
    amide
    301. Quinoxaline-2-carboxylic acid [1(S)- 115-117 533
    benzyl-2(S)-hydroxy-4(S)-
    hydroxycarbamoyl-4-(1-hydroxy-4-
    propyl-cyclohexyl)-butyl]-amide
    302. Quinoxaline-2-carboxylic acid [1(S)- 500,
    benzyl-4(R)-carbamoyl-2(S)-hydroxy-5- 483
    (4-methoxy-phenyl)-pentyl]-amide
    303. Quinoxaline-2-carboxylic acid [1(S)- 246-248 504
    benzyl-4(S)-carbamoyl-4(S)-(4-ethyl-1-
    hydroxy-cyclohexyl)-2-hydroxy-butyl]-
    amide
    304. Quinoxaline-2-carboxylic acid [1(S)- 210-211 505
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-
    (1-hydroxy-4,4-dimethyl-cyclohexyl)-
    butyl]-amide
    305. Quinoxaline-2-carboxylic acid [1(S)- 118-123 520
    benzyl-2(S)-hydroxy-4(S)-
    hydroxycarbamoyl-4-(1-hydroxy-4,4-
    dimethyl-cyclohexyl)-but yl]-amide
    306. Quinoxaline-2-carboxylic acid [1(S)- 207.5-208.5
    benzyl-4(S)-carbamoyl-4-(4,4-difluoro-
    1-hydroxy-cyclohexyl)-2(S)-hydroxy-
    butyl]-amide
    307. Quinoxaline-2-carboxylic acid [1(S)- 130-131 572
    benzyl-4(S)-(4,4-difluoro-1-hydroxy-
    cyclohexyl)-2(S)-hydroxy-4-
    hydroxycarbamoyl-but yl]-amide
    308. Quinoxaline-2-carboxylic acid [1(S)- 250-252 545
    benzyl-4(S)-carbamoyl-2(S)-hydroxy-4-
    (1-hydroxy-4-trifluoromethyl-
    cyclohexyl)-butyl]-amide
    309. Quinoxaline-3-carboxylic acid 1(S)- 94-98 454
    cyclohexylmethyl-2(S)-hydroxy-6-
    methyl-4(R)-methylcarbamoyl-heptyl)-
    amide
    310. Quinoxaline-2-carboxylic acid [1(S)-   174-175.5 522
    benzyl-7-fluoro-2(S)-hydroxy-7-methyl-
    4(R)-(pyrrolidine-1-carbonyl)-octyl]-
    amide
    311. N-(1(S)-Benzyl-4(S)-carbamoyl-4- 218-220 470
    cyclohexyl-2(S)-hydroxy-butyl)-5-
    bromo-nicotinamide
    312. Quinoxaline-2-carboxylic acid (1(S)- 147-149 482, 467
    benzyl-7-fluoro-4(R)-
    hydrazinocarbonyl-2(S)-hydroxyl-7-
    methyl-octyl)-amide

Claims (38)

1. A compound of the formula
Figure US20020198207A1-20021226-C00012
wherein R1 is (C2-C9)heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-N H-(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)-(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
R2 is phenyl-(CH2)m—, naphthyl-(CH2)m—, (C3-C10)cycloalkyl-(CH2)m—, (C1-C6)alkyl or (C2-C9)heteroaryl-(CH2)m—, wherein m is an interger from zero to four; wherein each of said phenyl, naphthyl, (C3-C10)cycloalkyl or (C2-C9)heteroaryl moieties of said phenyl-(CH2)m—, naphthyl-(CH2)m—, (C3-C10)cycloalkyl-(CH2)m— or (C2-C9)heteroaryl-(CH2)m— groups may optionally be substituted with one or more substituents independently selected from hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)-(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, phenoxy, benzyloxy, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
R3 is hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl-(CH2)n—, (C2-C9)heterocycloalkyl-(CH2)n—, (C2-C9)heteroaryl-(CH2)n— or aryl-(CH2)n—; wherein n is an interger from zero to six;
wherein said R3 (C1-C10)alkyl group may optionally be substituted with one or more substituents, independently selected from hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)-(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2-(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl; and wherein any of the carbon-carbon single bonds of said (C1-C10)alkyl may optionally be replaced by a carbon-carbon double bond;
wherein the (C3-C10)cycloalkyl moiety of said R3 (C3-C10)cycloalkyl-(CH2)n— group may optionally be substituted by one to three substitutents independently selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alky](O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkyl HN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3-phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
wherein the (C2-C9)heterocycloalkyl moiety of said R3 (C2-C9)heterocycloalkyl-(CH2)n— group may contain from one to three heteroatoms independently selected from nitrogen, sulfur, oxygen, >S(═O), >SO2 or >NR6, wherein said (C2-C9)heterocycloalkyl moiety of said (C2-C9)heterocycloalkyl-(CH2)n— group may optionally be substituted on any of the ring carbon atoms capable of forming an additional bond with a substituent independently selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, H0-(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
wherein the (C2-C9)heteroaryl moiety of said R3 (C2-C9)heteroaryl-(CH2)n— group may contain from one to three heteroatoms independently selected from nitrogen, sulfur or oxygen wherein said (C2-C9)heteroaryl moiety of said (C2-C9)heteroaryl-(CH2)n— group may optionally be substituted on any of the ring carbon atoms capable of forming an additional bond with a substituent selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C8)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl; and
wherein said aryl moiety of said R3 aryl-(CH2)n— group is optionally substituted phenyl or naphthyl, wherein said phenyl and naphthyl may optionally be substituted with from one to three substituents independently selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
or R3 and the carbon to which it is attached form a five to seven membered carbocyclic ring, wherein any of the carbon atoms of said five membered carbocyclic ring may optionally be substituted with a substituent selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)-(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[N H](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl; wherein one of the carbon-carbon bonds of said five to seven membered carbocyclic ring may optionally be fused to an optionally substituted phenyl ring, wherein said substitutents may be independently selected from hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6)alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)-(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
R4 is hydrogen, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C═O)—, (C3-C10)cycloalkyl-(CH2)p—, (C2-C9)heterocycloalkyl-(CH2)p—, (C2-C9)heteroaryl-(CH2)p—, phenyl-(CH2)p—, or naphthyl-(CH2)p—, wherein p is an integer from zero to four; wherein said (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl, phenyl and naphthyl groups of said (C2-C9)heterocycloalkyl-(CH2)p—, (C2-C9)heteroaryl-(CH2)p—, phenyl-(CH2)p—, or naphthyl-(CH2)p— may be optionally substituted on any of the ring atoms capable of supporting an additional bond with a substituent selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6) alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2 amino, amino(C1-C6)alkyl, (C1-C6)alkylamino (C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
or R4 and R5 together with the nitrogen atom to which they are attached form a (C2-C9)heterocycloalkyl group wherein any of the ring atoms of said (C2-C9)heterocycloalkyl group may optionally be substituted with a substituent selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, HO—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-O—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—O—(C1-C6)alkyl, H(O═C)—, H(O═C)—(C1-C6)alkyl, (C1-C6) alkyl(O═C)—, (C1-C6)alkyl(O═C)—(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2 amino, amino(C1-C6)alkyl, (C1-C6)alkylamino (C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2N—(C═O)—, H2N(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-HN(C═O)—(C1-C6)alkyl, [(C1-C6)alkyl]2N—(C═O)—(C1-C6)alkyl, H(O═C)—NH—, (C1-C6)alkyl(C═O)—NH, (C1-C6)alkyl(C═O)—[NH](C1-C6)alkyl, (C1-C6)alkyl(C═O)—[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-SO2—NH—, H2N—SO2—, H2N—SO2—(C1-C6)alkyl, (C1-C6)alkylHN—SO2—(C1-C6)alkyl, [(C1-C6)alkyl]2N—SO2—(C1-C6)alkyl, CF3SO3—, (C1-C6)alkyl-SO3—, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
R5 is hydrogen, (C1-C6)alkyl or amino;
R6 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy-(CH2)9—, (C1-C6)alkoxy(C═O)—(CH2)g—, (C1-C6)alkyl-(SO2)—(CH2)9—, (C6-C10)aryloxy-(CH2)g—, (C6-C10)aryloxy(C═O)—(CH2)g—, and (C6-C10)aryl-(SO2)—(CH2)9—, wherein g is an integer from 1 to four;
with the proviso that when either R4 or R5 is hydrogen, and the other of R4 or R5 is (C1-C6)alkyl, R2 is (C3-C10)cycloalkyl or isopropyl and R3is (C3-C5)alkyl, phenyl, methylvinyl, dimethylvinyl, halovinyl, hydroxy(C1-C3)alkyl or amino(C1-C4)alkyl then R1 must be other than indol-5-yl, 6-azaindol-2-yl, 2,3-dichloro-pyrol-5-yl, 4-hydroxyquinolin-3-yl, 2-hydroxyquinoxalin-3-yl, 6-azaindolin-3-yl, or optionally substituted indol-2 or 3-yl;
and the pharmaceutically acceptable salts of such compounds.
2. A compound according to claim 1, wherein said compound of formula I has the exact stereochemistry depicted in formula
Figure US20020198207A1-20021226-C00013
wherein R1, R2, R3, R4 and R5 are as described in claim 1.
3. A compound according to claim 1, wherein R1 is optionally substituted pyrazolo[3,4-b]pyridinyl, cinnolinyl, pyridinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzothiazolyl, indolyl, pyrazinyl, benzoimidazolyl, benzofuranyl, benzo[b]thiophenyl, naphthalenyl, quinoxalinyl, isoquinolinyl, 5,6,7,8-tetrahydro-quinolin-3-yl or quinolinyl.
4. A compound according to claim 2, wherein R1 is optionally substituted pyrazolo[3,4-b]pyridinyl, cinnolinyl, pyridinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzothiazolyl, indolyl, pyrazinyl, benzoimidazolyl, benzofuranyl, benzo[b]thiophenyl, naphthalenyl, quinoxalinyl, isoquinolinyl, 5,6,7,8-tetrahydro-quinolin-3-yl or quinolinyl.
5. A compound according to claim 1, wherein R1 is optionally substituted pyrazolo[3,4-b]pyridin-5-yl, cinnolin-4-yl, pyridin-2-yl, 6,7-dihydro-5H-[1]pyrindin-3-yl, benzothiazol-2-yl, indol-2-yl, pyrazin-2-yl, benzoimidazol-2-yl, benzofuran-2-yl, benzo[b]thiophen-2-yl, naphthalen-2-yl, quinoxalin-2-yl, quinoxalin-6-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, 5,6,7,8-tetrahydro-quinolin-3-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl.
6. A compound according to claim 2, wherein R1 is optionally substituted pyrazolo[3,4-b]pyridin-5-yl, cinnolin-4-yl, pyridin-2-yl, 6,7-dihydro-5H-[1]pyrindin-3-yl, benzothiazol-2-yl, indol-2-yl, pyrazin-2-yl, benzoimidazol-2-yl, benzofuran-2-yl, benzo[b]thiophen-2-yl, naphthalen-2-yl, quinoxalin-2-yl, quinoxalin-6-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, 5,6,7,8-tetrahydro-quinolin-3-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl.
7. A compound according to claim 1, wherein R1 is optionally substituted quinoxalin-2-yl, quinoxalin-6-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl.
8. A compound according to claim 2, wherein R1 is optionally substituted quinoxalin-2-yl, quinoxalin-6-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl.
9. A compound according to claim 1, wherein R2 is optionally substituted benzyl.
10. A compound according to claim 2, wherein R2 is optionally substituted benzyl.
11. A compound according to claim 3, wherein R2 is optionally substituted benzyl.
12. A compound according to claim 4, wherein R2 is optionally substituted benzyl.
13. A compound according to claim 5, wherein R2 is optionally substituted benzyl.
14. A compound according to claim 6, wherein R2 is optionally substituted benzyl.
15. A compound according to claim 7, wherein R2 is optionally substituted benzyl.
16. A compound according to claim 8, wherein R2 is optionally substituted benzyl.
17. A compound according to claim 1, wherein R3 is optionally substituted (C1-C10)alkyl or (C3-C10)cycloalkyl-(CH2)n—.
18. A compound according to claim 2, wherein R3 is optionally substituted (C1-C10)alkyl or (C3-C10)cycloalkyl-(CH2)n—.
19. A compound according to claim 6, wherein R3 is optionally substituted (C1-C10)alkyl or (C3-C10)cycloalkyl-(CH2)n—.
20. A compound according to claim 8, wherein R3 is optionally substituted (C1-C10)alkyl or (C3-C10)cycloalkyl-(CH2)n—.
21. A compound according to claim 1, wherein R3 is optionally substituted n-butyl, t-butyl, isobutyl, n-pentyl, 2-methyl-pentyl, cyclopentyl, or cyclohexyl.
22. A compound according to claim 2, wherein R3 is optionally substituted n-butyl, t-butyl, isobutyl, n-pentyl, 2-methyl-pentyl, cyclopentyl, or cyclohexyl.
23. A compound according to claim 6, wherein R3 is optionally substituted n-butyl, t-butyl, isobutyl, n-pentyl, 2-methyl-pentyl, cyclopentyl, or cyclohexyl.
24. A compound according to claim 8, wherein R3 is optionally substituted n-butyl, t-butyl, isobutyl, n-pentyl, 2-methyl-pentyl, cyclopentyl, or cyclohexyl.
25. A compound according to claim 1, wherein R3 is substituted by fluoro or hydroxy.
26. A compound according to claim 2, wherein R3 is substituted by fluoro or hydroxy.
27. A compound according to claim 1, wherein R3 is 4,4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, isobutyl, or 1-hydroxy-cyclohexyl.
28. A compound according to claim 2, wherein R3 is 4,4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, isobutyl, or 1-hydroxy-cyclohexyl.
29. A compound according to claim 6, wherein R3 is 4,4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, isobutyl, or 1-hydroxy-cyclohexyl.
30. A compound according to claim 8, wherein R3 is 4,4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, isobutyl, or 1-hydroxy-cyclohexyl.
31. A compound according to claim 16, wherein R3 is 4,4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, isobutyl, or 1-hydroxy-cyclohexyl.
32. A compound according to claim 1, wherein said compound is:
7,8-difluoro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;
8-fluoro-quinoline-3-carboxylic acid 1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;
quinoxaline-2-carboxylic acid [4(R)-carbamoyl-7-fluoro-1-(3(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;
quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1-(2(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;
quinoxaline-2-carboxylic acid [I (S)-benzyl-4(S)-carbamoyl-4(S)-(2,6-dimethyl-tetrahydro-pyran-4-yl)-2(S)-hydroxy-butyl]-amide;
quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide;
quinoxaline-2-carboxylic acid 1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide;
quinoxaline-2-carboxylic acid 1(S)-cyclohexylmethyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;
quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;
quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-(4,4-difluoro-1-hydroxy-cyclohexyl)-2(S)-hydroxy-4-hydroxycarbamoyl-but yl]-amide;
quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-carbamoyl-4(S)-(4,4-difluoro-cyclohexyl)-2(S)-hydroxy-butyl]-amide;
quinoline-3-carboxylic acid (1(S)-benzyl-4(S)-carbamoyl-4-cyclohexyl-2(S)-hydroxy-butyl)-amide;
quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiophen-2-ylmethyl-octyl)-amide;
quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-chloro-2(S)-hydroxy-oct-6-enyl)-amide;
quinoxaline-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-phenyl-pentyl)-amide;
N-1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-5,6-dichloro-nicotinamide;
quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiazol-4(R)-ylmethyl-octyl)-amide;
benzothiazole-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide; or
benzofuran-2-carboxylic acid 1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide.
33. A pharmaceutical composition for treating or preventing a disorder or condition selected from autoimmune diseases, acute and chronic inflammatory conditions, allergic conditions, infection associated with inflammation, viral, transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity, and granulomatous in a mammal, comprising an amount of a compound according to claim 1 that is effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier.
34. A pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by inhibiting MIP-1α binding to the receptor CCR1 in a mammal, comprising an amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier.
35. A method for treating or preventing a disorder or condition selected from autoimmune diseases, acute and chronic inflammatory conditions, allergic conditions, infection associated with inflammation, viral, transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity, and granulomatous in a mammal, comprising administering to a mammal in need of such treatment or prevention an amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder or condition.
36. A method for treating or preventing a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal, comprising administering to a mammal in need of such treatment or prevention an amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder or condition.
37. A pharmaceutical composition for treating or preventing a disorder or condition selected from autoimmune diseases, acute and chronic inflammatory conditions, allergic conditions, infection associated with inflammation, viral, transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity, and granulomatous in a mammal, comprising a CCR1 receptor antagonizing effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
38. A pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal, comprising a CCR1 receptor antagonizing effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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